1-75848189-C-T

Variant names:

• chr1-75848189-C-T
• rs2047435
• NM_002440.4:c.1163-20C>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.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
• Publications: 8 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=-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 rank	MANE	Protein	UniProt
MSH4	NM_002440.4	c.1163-20C>T		intron_variant	Intron 7 of 19	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.1163-20C>T		intron_variant	Intron 7 of 19	1	NM_002440.4	ENSP00000263187.3

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

GnomAD2 exomes AF: 0.192 AC: 46345 AN: 240992 AF XY: 0.178

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 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

African (AFR) AF: 0.288 AC: 8984 AN: 31160

American (AMR) AF: 0.368 AC: 15495 AN: 42142

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2708 AN: 25318

East Asian (EAS) AF: 0.298 AC: 11665 AN: 39116

South Asian (SAS) AF: 0.101 AC: 8264 AN: 81632

European-Finnish (FIN) AF: 0.190 AC: 10120 AN: 53196

Middle Eastern (MID) AF: 0.128 AC: 711 AN: 5566

European-Non Finnish (NFE) AF: 0.137 AC: 142992 AN: 1046778

Other (OTH) AF: 0.153 AC: 8790 AN: 57580

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

African (AFR) AF: 0.300 AC: 12441 AN: 41422

American (AMR) AF: 0.276 AC: 4210 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1424 AN: 5180

South Asian (SAS) AF: 0.101 AC: 488 AN: 4816

European-Finnish (FIN) AF: 0.193 AC: 2038 AN: 10554

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.145 AC: 9864 AN: 67946

Other (OTH) AF: 0.191 AC: 403 AN: 2112

Alfa AF: 0.177 Hom.: 692

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
PhyloP100		-0.043
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: rs2047435; hg19: chr1-76313874;