rs1021462

chr1-75910469-G-Achr1-75910469-G-Cchr1-75910469-G-T

Variant summary

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

The NM_002440.4(MSH4):c.2620-2227G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 150,824 control chromosomes in the GnomAD database, including 19,232 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19232 hom., cov: 29)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99

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 (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH4	NM_002440.4	c.2620-2227G>A		intron_variant		ENST00000263187.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH4	ENST00000263187.4	c.2620-2227G>A		intron_variant		1	NM_002440.4	P1

Frequencies

GnomAD3 genomes AF: 0.495 AC: 74590 AN: 150708 Hom.: 19199 Cov.: 29

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.502

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.495 AC: 74685 AN: 150824 Hom.: 19232 Cov.: 29 AF XY: 0.496 AC XY: 36516 AN XY: 73664

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.318

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.504

Alfa AF: 0.474 Hom.: 2115

Bravo AF: 0.506

Asia WGS AF: 0.328 AC: 1140 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.17
Dann	Benign	0.43

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: rs1021462; hg19: chr1-76376154; COSMIC: COSV54213421;