1-75867478-T-G

Position:

• chr1-75867478-T-G

Variant summary

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

The NM_002440.4(MSH4):​c.1231-36T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,090,396 control chromosomes in the GnomAD database, including 29,667 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 (3526 hom., cov: 31)
  • Exomes 𝑓: 0.23 (26141 hom.)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860

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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH4	NM_002440.4	c.1231-36T>G		intron_variant		ENST00000263187.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH4	ENST00000263187.4	c.1231-36T>G		intron_variant		1	NM_002440.4	P1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31914 AN: 151984 Hom.: 3529 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.203 AC: 46464 AN: 228534 Hom.: 5175 AF XY: 0.206 AC XY: 25633 AN XY: 124182

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.228 AC: 213574 AN: 938296 Hom.: 26141 Cov.: 12 AF XY: 0.226 AC XY: 110263 AN XY: 488410

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.210 AC: 31919 AN: 152100 Hom.: 3526 Cov.: 31 AF XY: 0.207 AC XY: 15381 AN XY: 74364

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.216

Alfa AF: 0.204 Hom.: 1816

Bravo AF: 0.207

Asia WGS AF: 0.152 AC: 527 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.47
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs5745433; hg19: chr1-76333163;