rs3819949

chr1-75888395-C-T

Variant summary

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

The NM_002440.4(MSH4):c.2108-856C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 151,834 control chromosomes in the GnomAD database, including 37,470 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 0.70 (37470 hom., cov: 30)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH4	NM_002440.4	c.2108-856C>T		intron_variant		ENST00000263187.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH4	ENST00000263187.4	c.2108-856C>T		intron_variant		1	NM_002440.4	P1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105506 AN: 151718 Hom.: 37430 Cov.: 30

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.709

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

GnomAD4 genome AF: 0.696 AC: 105605 AN: 151834 Hom.: 37470 Cov.: 30 AF XY: 0.692 AC XY: 51403 AN XY: 74232

Gnomad4 AFR AF: 0.793

Gnomad4 AMR AF: 0.736

Gnomad4 ASJ AF: 0.709

Gnomad4 EAS AF: 0.313

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.711

Alfa AF: 0.697 Hom.: 4943

Bravo AF: 0.705

Asia WGS AF: 0.480 AC: 1660 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.3
Dann	Benign	0.53

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: rs3819949; hg19: chr1-76354080;