Genetic Variant NM_001145641.2:c.155C>G (chr19-43612276-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001145641.2(SRRM5):c.155C>G(p.Ser52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000838 in 1,551,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

SRRM5
NM_001145641.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.501

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=0.023638368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRM5	NM_001145641.2 link	c.155C>G	p.Ser52Cys	missense_variant	Exon 1 of 1	ENST00000417606.3	NP_001139113.1	B3KS81Q4G0Z0
ZNF428	NM_182498.4 link	c.76+1953G>C		intron_variant	Intron 2 of 2	ENST00000300811.8	NP_872304.2	Q96B54I6L9C8
ZNF428	XM_047438168.1 link	c.76+1953G>C		intron_variant	Intron 3 of 3		XP_047294124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SRRM5	ENST00000417606.3 link	c.155C>G	p.Ser52Cys	missense_variant	Exon 1 of 1	6	NM_001145641.2	ENSP00000414512.1	B3KS81
ZNF428	ENST00000300811.8 link	c.76+1953G>C		intron_variant	Intron 2 of 2	1	NM_182498.4	ENSP00000300811.2	Q96B54
SRRM5	ENST00000607544.1 link	c.155C>G	p.Ser52Cys	missense_variant	Exon 3 of 3	2		ENSP00000476253.1	B3KS81
ZNF428	ENST00000598676.1 link	c.76+1953G>C		intron_variant	Intron 2 of 3	5		ENSP00000469484.1	M0QXZ5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000454

AC:

AN:

154138

Hom.:

AF XY:

0.0000489

AC XY:

AN XY:

81784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000642

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000715

AC:

AN:

1399436

Hom.:

Cov.:

AF XY:

0.00000724

AC XY:

AN XY:

690234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000196

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155C>G (p.S52C) alteration is located in exon 1 (coding exon 1) of the SRRM5 gene. This alteration results from a C to G substitution at nucleotide position 155, causing the serine (S) at amino acid position 52 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

0.14

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.0026

T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.39

.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.49

.;N

REVEL

Benign

0.060

Sift

Benign

0.043

.;D

Sift4G

Benign

0.070

T;T

Polyphen

0.99

D;D

Vest4

0.048

MutPred

0.16

Loss of phosphorylation at S52 (P = 0.0035);Loss of phosphorylation at S52 (P = 0.0035);

MVP

0.040

MPC

0.066

ClinPred

0.15

GERP RS

2.4

Varity_R

0.064

gMVP

0.025

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