rs1021462

Variant names:

• chr1-75910469-G-A
• rs1021462
• NM_002440.4:c.2620-2227G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-75910469-G-A
• chr1-75910469-G-C
• chr1-75910469-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

MSH4 Gene-Disease associations (from GenCC):

• premature ovarian failure 20

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MSH4	NM_002440.4	c.2620-2227G>A		intron_variant	Intron 19 of 19	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.2620-2227G>A		intron_variant	Intron 19 of 19	1	NM_002440.4	ENSP00000263187.3

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

African (AFR) AF: 0.635 AC: 26107 AN: 41102

American (AMR) AF: 0.514 AC: 7777 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1885 AN: 3464

East Asian (EAS) AF: 0.299 AC: 1527 AN: 5112

South Asian (SAS) AF: 0.318 AC: 1509 AN: 4752

European-Finnish (FIN) AF: 0.518 AC: 5329 AN: 10284

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29098 AN: 67694

Other (OTH) AF: 0.504 AC: 1050 AN: 2082

Alfa AF: 0.480 Hom.: 2271

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
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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