Variant chr19-43612639-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145641.2(SRRM5):c.518A>G(p.Tyr173Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,551,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SRRM5
NM_001145641.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.388

Variant links:

Genes affected

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

SRRM5 links:

ZNF428 (HGNC:20804): (zinc finger protein 428) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZNF428 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025874138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRRM5	NM_001145641.2 linkuse as main transcript	c.518A>G	p.Tyr173Cys	missense_variant	1/1	ENST00000417606.3	NP_001139113.1	B3KS81Q4G0Z0
ZNF428	NM_182498.4 linkuse as main transcript	c.76+1590T>C		intron_variant		ENST00000300811.8	NP_872304.2	Q96B54I6L9C8
ZNF428	XM_047438168.1 linkuse as main transcript	c.76+1590T>C		intron_variant			XP_047294124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SRRM5	ENST00000417606.3 linkuse as main transcript	c.518A>G	p.Tyr173Cys	missense_variant	1/1	6	NM_001145641.2	ENSP00000414512.1	B3KS81
ZNF428	ENST00000300811.8 linkuse as main transcript	c.76+1590T>C		intron_variant		1	NM_182498.4	ENSP00000300811.2	Q96B54
SRRM5	ENST00000607544.1 linkuse as main transcript	c.518A>G	p.Tyr173Cys	missense_variant	3/3	2		ENSP00000476253.1	B3KS81
ZNF428	ENST00000598676.1 linkuse as main transcript	c.76+1590T>C		intron_variant		5		ENSP00000469484.1	M0QXZ5

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000137

AC:

AN:

153632

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

81488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000598

Gnomad NFE exome

AF:

0.000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000174

AC:

243

AN:

1399120

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

125

AN XY:

690022

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000815

Gnomad4 NFE exome

AF:

0.000176

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000283

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000466

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.000176

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.518A>G (p.Y173C) alteration is located in exon 1 (coding exon 1) of the SRRM5 gene. This alteration results from a A to G substitution at nucleotide position 518, causing the tyrosine (Y) at amino acid position 173 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0027

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.57

.;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.81

.;N

REVEL

Benign

0.021

Sift

Benign

0.040

.;D

Sift4G

Benign

0.065

T;T

Polyphen

0.056

B;B

Vest4

0.16

MVP

0.040

MPC

0.017

ClinPred

0.046

GERP RS

0.52

Varity_R

0.10

gMVP

0.033

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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