1-75803775-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002440.4(MSH4):c.289G>A(p.Ala97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,597,556 control chromosomes in the GnomAD database, including 62,527 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6119 hom., cov: 32)
  • Exomes 𝑓: 0.27 (56408 hom.)
• Consequence: MSH4 NM_002440.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.864

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055417717).
• BP6: Variant 1-75803775-G-A is Benign according to our data. Variant chr1-75803775-G-A is described in ClinVar as [Benign]. Clinvar id is 2585667.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH4	NM_002440.4	c.289G>A	p.Ala97Thr	missense_variant	2/20	ENST00000263187.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH4	ENST00000263187.4	c.289G>A	p.Ala97Thr	missense_variant	2/20	1	NM_002440.4	P1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42055 AN: 151886 Hom.: 6118 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.0265

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.260 AC: 61701 AN: 236992 Hom.: 9028 AF XY: 0.263 AC XY: 33625 AN XY: 128050

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.0185

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.273 AC: 394433 AN: 1445552 Hom.: 56408 Cov.: 32 AF XY: 0.273 AC XY: 196206 AN XY: 718640

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.0379

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.277 AC: 42069 AN: 152004 Hom.: 6119 Cov.: 32 AF XY: 0.275 AC XY: 20448 AN XY: 74292

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.0268

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.302

Alfa AF: 0.291 Hom.: 17323

Bravo AF: 0.274

TwinsUK AF: 0.258 AC: 958

ALSPAC AF: 0.297 AC: 1146

ESP6500AA AF: 0.300 AC: 1324

ESP6500EA AF: 0.299 AC: 2572

ExAC AF: 0.262 AC: 31826

Asia WGS AF: 0.140 AC: 488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spermatogenic failure 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Premature ovarian failure 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.3
Dann	Benign	0.91
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.13
Sift	Benign	0.18	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.021
MPC		0.068
ClinPred		0.0058	T
GERP RS		0.63
Varity_R		0.040
gMVP		0.36

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: rs5745325; hg19: chr1-76269460; COSMIC: COSV54199963;