4-56491517-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006947.4(SRP72):c.1589T>C(p.Ile530Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,613,966 control chromosomes in the GnomAD database, including 120 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. I530V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 110 hom. )

Consequence

SRP72
NM_006947.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.62

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008755773).

BP6

Variant 4-56491517-T-C is Benign according to our data. Variant chr4-56491517-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00179 (273/152312) while in subpopulation SAS AF = 0.0385 (186/4830). AF 95% confidence interval is 0.034. There are 10 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP72	NM_006947.4 link	c.1589T>C	p.Ile530Thr	missense_variant	Exon 16 of 19	ENST00000642900.1	NP_008878.3	O76094-1V9HWK0
SRP72	NM_001267722.2 link	c.1406T>C	p.Ile469Thr	missense_variant	Exon 14 of 17		NP_001254651.1	O76094-2
SRP72	XM_024454192.2 link	c.1589T>C	p.Ile530Thr	missense_variant	Exon 16 of 17		XP_024309960.1
SRP72	NR_151856.2 link	n.1608T>C		non_coding_transcript_exon_variant	Exon 16 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1 link	c.1589T>C	p.Ile530Thr	missense_variant	Exon 16 of 19		NM_006947.4	ENSP00000495128.1		O76094-1

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

263

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0389

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00499

AC:

1253

AN:

251322

AF XY:

0.00676

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00343

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00237

AC:

3462

AN:

1461654

Hom.:

110

Cov.:

AF XY:

0.00333

AC XY:

2419

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33472

American (AMR)

AF:

0.000157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00320

AC:

127

AN:

39648

South Asian (SAS)

AF:

0.0351

AC:

3023

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1111890

Other (OTH)

AF:

0.00349

AC:

211

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

155

311

466

622

777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00179

AC:

273

AN:

152312

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41568

American (AMR)

AF:

0.00144

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00270

AC:

AN:

5182

South Asian (SAS)

AF:

0.0385

AC:

186

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

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:

0.000979

Hom.:

Bravo

AF:

0.000782

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00564

AC:

685

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 24, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant aplasia and myelodysplasia

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.042

T;.;T

Eigen

Benign

-0.0077

Eigen_PC

Benign

0.087

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D;.

MetaRNN

Benign

0.0088

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.83

L;.;L

PhyloP100

7.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.46

Sift

Benign

0.097

T;D;.

Sift4G

Benign

0.19

T;T;.

Polyphen

0.77

P;.;P

Vest4

0.41

MVP

0.90

MPC

0.33

ClinPred

0.024

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.081

gMVP

0.22

Mutation Taster

=96/4

polymorphism

(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