rs5745433

Variant names:

• chr1-75867478-T-G
• rs5745433
• NM_002440.4:c.1231-36T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-75867478-T-G
• chr1-75867478-T-C

Variant summary

Our verdict is Benign. The variant received -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. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002440.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH4	NM_002440.4	MANE Select	c.1231-36T>G		intron	N/A	NP_002431.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH4	ENST00000263187.4	TSL:1 MANE Select	c.1231-36T>G		intron	N/A	ENSP00000263187.3	O15457

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

GnomAD2 exomes AF: 0.203 AC: 46464 AN: 228534 AF XY: 0.206

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 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

African (AFR) AF: 0.158 AC: 3533 AN: 22326

American (AMR) AF: 0.181 AC: 6412 AN: 35520

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 3987 AN: 22282

East Asian (EAS) AF: 0.0156 AC: 578 AN: 37092

South Asian (SAS) AF: 0.184 AC: 13114 AN: 71314

European-Finnish (FIN) AF: 0.213 AC: 11260 AN: 52860

Middle Eastern (MID) AF: 0.234 AC: 1089 AN: 4648

European-Non Finnish (NFE) AF: 0.253 AC: 163999 AN: 649272

Other (OTH) AF: 0.223 AC: 9602 AN: 42982

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

African (AFR) AF: 0.160 AC: 6627 AN: 41492

American (AMR) AF: 0.227 AC: 3470 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3466

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5190

South Asian (SAS) AF: 0.185 AC: 893 AN: 4822

European-Finnish (FIN) AF: 0.215 AC: 2272 AN: 10588

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17135 AN: 67960

Other (OTH) AF: 0.216 AC: 455 AN: 2108

Alfa AF: 0.207 Hom.: 2050

Bravo AF: 0.207

Asia WGS AF: 0.152 AC: 527 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.47
DANN	Benign	0.74
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs5745433; hg19: chr1-76333163;