chr4-56491517-T-C

Position:

chr4-56491517-T-C

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SRP72	NM_006947.4 linkuse as main transcript	c.1589T>C	p.Ile530Thr	missense_variant	16/19	ENST00000642900.1	NP_008878.3
SRP72	NM_001267722.2 linkuse as main transcript	c.1406T>C	p.Ile469Thr	missense_variant	14/17		NP_001254651.1
SRP72	XM_024454192.2 linkuse as main transcript	c.1589T>C	p.Ile530Thr	missense_variant	16/17		XP_024309960.1
SRP72	NR_151856.2 linkuse as main transcript	n.1608T>C		non_coding_transcript_exon_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1 linkuse as main transcript	c.1589T>C	p.Ile530Thr	missense_variant	16/19		NM_006947.4	ENSP00000495128	P1	O76094-1
SRP72	ENST00000510663.6 linkuse as main transcript	c.1406T>C	p.Ile469Thr	missense_variant	14/17	1		ENSP00000424576		O76094-2
SRP72	ENST00000646579.1 linkuse as main transcript	n.600T>C		non_coding_transcript_exon_variant	6/6
SRP72	ENST00000647432.1 linkuse as main transcript	n.691T>C		non_coding_transcript_exon_variant	4/5

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

GnomAD3 exomes

AF:

0.00499

AC:

1253

AN:

251322

Hom.:

AF XY:

0.00676

AC XY:

918

AN XY:

135824

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 SAS exome

AF:

0.0374

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

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00320

Gnomad4 SAS exome

AF:

0.0351

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.00349

GnomAD4 genome

AF:

0.00179

AC:

273

AN:

152312

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.0385

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.000807

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 24, 2018

- -

Autosomal dominant aplasia and myelodysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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

MutationTaster

Benign

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over