chr4-56467693-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_006947.4(SRP72):c.58C>T(p.Arg20Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00408 in 1,554,546 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0042 ( 19 hom. )

Consequence

SRP72
NM_006947.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.75

Publications

9 publications found

Variant links:

Genes affected

SRP72 (HGNC:11303): (signal recognition particle 72) This gene encodes the 72 kDa subunit of the signal recognition particle (SRP), a ribonucleoprotein complex that mediates the targeting of secretory proteins to the endoplasmic reticulum (ER). The SRP complex consists of a 7S RNA and 6 protein subunits: SRP9, SRP14, SRP19, SRP54, SRP68, and SRP72, that are bound to the 7S RNA as monomers or heterodimers. SRP has at least 3 distinct functions that can be associated with the protein subunits: signal recognition, translational arrest, and ER membrane targeting by interaction with the docking protein. Mutations in this gene are associated with familial bone marrow failure. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

SRP72 Gene-Disease associations (from GenCC):

autosomal dominant aplasia and myelodysplasia
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

SRP72 links:

ENSG00000289393 (HGNC:):

ENSG00000289393 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.01167652).

BP6

Variant 4-56467693-C-T is Benign according to our data. Variant chr4-56467693-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 349117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP72	NM_006947.4 link	c.58C>T	p.Arg20Trp	missense_variant	Exon 1 of 19	ENST00000642900.1	NP_008878.3	O76094-1V9HWK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1 link	c.58C>T	p.Arg20Trp	missense_variant	Exon 1 of 19		NM_006947.4	ENSP00000495128.1		O76094-1

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

440

AN:

150982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000950

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00276

Gnomad ASJ

AF:

0.00145

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00189

Gnomad FIN

AF:

0.000777

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00485

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00260

AC:

534

AN:

205648

AF XY:

0.00277

show subpopulations

Gnomad AFR exome

AF:

0.000926

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.000916

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000949

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00421

AC:

5909

AN:

1403452

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

2874

AN XY:

697408

show subpopulations

African (AFR)

AF:

0.000911

AC:

AN:

29638

American (AMR)

AF:

0.00205

AC:

AN:

36146

Ashkenazi Jewish (ASJ)

AF:

0.000652

AC:

AN:

24534

East Asian (EAS)

AF:

0.00

AC:

AN:

33452

South Asian (SAS)

AF:

0.00190

AC:

153

AN:

80468

European-Finnish (FIN)

AF:

0.00139

AC:

AN:

51672

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00494

AC:

5358

AN:

1084238

Other (OTH)

AF:

0.00352

AC:

203

AN:

57682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

326

653

979

1306

1632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00291

AC:

440

AN:

151094

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

201

AN XY:

73792

show subpopulations

African (AFR)

AF:

0.000947

AC:

AN:

41174

American (AMR)

AF:

0.00276

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.00189

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.000777

AC:

AN:

10290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00485

AC:

329

AN:

67798

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00378

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00269

AC:

327

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SRP72: BS1, BS2 -

Autosomal dominant aplasia and myelodysplasia

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 24, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SRP72-related disorder

Benign:1

Mar 03, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;.;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

D;D;.;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.6

M;M;M;.

PhyloP100

4.7

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.3

D;D;.;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D;.;.

Sift4G

Pathogenic

0.0010

D;D;.;D

Polyphen

1.0

D;.;D;.

Vest4

0.62

MVP

0.68

MPC

0.54

ClinPred

0.035

GERP RS

5.5

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.56

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over