1-75912817-G-A

Position:

• chr1-75912817-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002440.4(MSH4):​c.2741G>A​(p.Ser914Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,586,522 control chromosomes in the GnomAD database, including 1,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.067 (490 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1332 hom.)
• Consequence: MSH4 NM_002440.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.636

Genes affected

MSH4 (HGNC:7327): (mutS homolog 4) This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015282333).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH4	NM_002440.4	c.2741G>A	p.Ser914Asn	missense_variant	20/20	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.2741G>A	p.Ser914Asn	missense_variant	20/20	1	NM_002440.4	ENSP00000263187.3

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10116 AN: 151752 Hom.: 482 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0596

GnomAD3 exomes AF: 0.0403 AC: 9231 AN: 229014 Hom.: 277 AF XY: 0.0387 AC XY: 4820 AN XY: 124530

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0292

Gnomad EAS exome AF: 0.00610

Gnomad SAS exome AF: 0.0314

Gnomad FIN exome AF: 0.0593

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0385 AC: 55180 AN: 1434652 Hom.: 1332 Cov.: 31 AF XY: 0.0382 AC XY: 27273 AN XY: 713428

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.00600

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0595

Gnomad4 NFE exome AF: 0.0370

Gnomad4 OTH exome AF: 0.0423

GnomAD4 genome AF: 0.0669 AC: 10158 AN: 151870 Hom.: 490 Cov.: 32 AF XY: 0.0661 AC XY: 4911 AN XY: 74244

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.0328

Gnomad4 FIN AF: 0.0596

Gnomad4 NFE AF: 0.0407

Gnomad4 OTH AF: 0.0585

Alfa AF: 0.0417 Hom.: 374

Bravo AF: 0.0676

TwinsUK AF: 0.0421 AC: 156

ALSPAC AF: 0.0343 AC: 132

ESP6500AA AF: 0.126 AC: 553

ESP6500EA AF: 0.0400 AC: 344

ExAC AF: 0.0436 AC: 5292

Asia WGS AF: 0.0340 AC: 116 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.21
Sift	Benign	0.38	T
Sift4G	Benign	0.18	T
Polyphen		0.41	B
Vest4		0.033
MPC		0.066
ClinPred		0.014	T
GERP RS		-0.34
Varity_R		0.055
gMVP		0.21

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

Other links and lift over

dbSNP: rs5745549; hg19: chr1-76378502; COSMIC: COSV54202121;