1-75848189-C-T

Position:

• chr1-75848189-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.1163-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,534,454 control chromosomes in the GnomAD database, including 22,497 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 0.21 (3808 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18689 hom.)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430

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=-0.7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH4	NM_002440.4	c.1163-20C>T		intron_variant		ENST00000263187.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH4	ENST00000263187.4	c.1163-20C>T		intron_variant		1	NM_002440.4	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31379 AN: 151848 Hom.: 3785 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.192 AC: 46345 AN: 240992 Hom.: 5717 AF XY: 0.178 AC XY: 23118 AN XY: 130012

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.267

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.152 AC: 209729 AN: 1382488 Hom.: 18689 Cov.: 25 AF XY: 0.149 AC XY: 103174 AN XY: 691504

Gnomad4 AFR exome AF: 0.288

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.207 AC: 31454 AN: 151966 Hom.: 3808 Cov.: 32 AF XY: 0.209 AC XY: 15524 AN XY: 74258

Gnomad4 AFR AF: 0.300

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.191

Alfa AF: 0.174 Hom.: 651

Bravo AF: 0.221

Asia WGS AF: 0.189 AC: 654 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.4
DANN	Benign	0.67

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: rs2047435; hg19: chr1-76313874;