Genetic Variant SRRM5:p.Val45Leu (chr19-43612254-G-C) – 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.133G>C(p.Val45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,551,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 7.1e-7 ( 0 hom. )

Consequence

SRRM5
NM_001145641.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.352

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=0.061568737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRM5	NM_001145641.2 link	c.133G>C	p.Val45Leu	missense_variant	Exon 1 of 1	ENST00000417606.3	NP_001139113.1	B3KS81Q4G0Z0
ZNF428	NM_182498.4 link	c.76+1975C>G		intron_variant	Intron 2 of 2	ENST00000300811.8	NP_872304.2	Q96B54I6L9C8
ZNF428	XM_047438168.1 link	c.76+1975C>G		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.133G>C	p.Val45Leu	missense_variant	Exon 1 of 1	6	NM_001145641.2	ENSP00000414512.1	B3KS81
ZNF428	ENST00000300811.8 link	c.76+1975C>G		intron_variant	Intron 2 of 2	1	NM_182498.4	ENSP00000300811.2	Q96B54
SRRM5	ENST00000607544.1 link	c.133G>C	p.Val45Leu	missense_variant	Exon 3 of 3	2		ENSP00000476253.1	B3KS81
ZNF428	ENST00000598676.1 link	c.76+1975C>G		intron_variant	Intron 2 of 3	5		ENSP00000469484.1	M0QXZ5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399428

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133G>C (p.V45L) alteration is located in exon 1 (coding exon 1) of the SRRM5 gene. This alteration results from a G to C substitution at nucleotide position 133, causing the valine (V) at amino acid position 45 to be replaced by a leucine (L). 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

0.19

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0057

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.45

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.28

.;N

REVEL

Benign

0.076

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.24

T;T

Polyphen

0.19

B;B

Vest4

0.088

MutPred

0.17

Gain of catalytic residue at V45 (P = 0.0651);Gain of catalytic residue at V45 (P = 0.0651);

MVP

0.014

MPC

0.054

ClinPred

0.34

GERP RS

1.1

Varity_R

0.083

gMVP

0.022

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