6-31741268-C-T

Variant summary

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

The NM_172166.4(MSH5):c.253C>T(p.Leu85Phe) variant causes a missense change. The variant allele was found at a frequency of 0.02 in 1,612,082 control chromosomes in the GnomAD database, including 690 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.035 (162 hom., cov: 31)
  • Exomes 𝑓: 0.018 (528 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.87

Genes affected

MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MSH5-SAPCD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016033947).
• BP6: Variant 6-31741268-C-T is Benign according to our data. Variant chr6-31741268-C-T is described in ClinVar as [Benign]. Clinvar id is 3056913.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH5	NM_172166.4	c.253C>T	p.Leu85Phe	missense_variant	3/25	ENST00000375750.9
MSH5-SAPCD1	NR_037846.1	n.381C>T		non_coding_transcript_exon_variant	3/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH5	ENST00000375750.9	c.253C>T	p.Leu85Phe	missense_variant	3/25	1	NM_172166.4	A2

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5276 AN: 151606 Hom.: 162 Cov.: 31

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00396

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0585

GnomAD3 exomes AF: 0.0250 AC: 6156 AN: 246592 Hom.: 192 AF XY: 0.0218 AC XY: 2928 AN XY: 134408

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.0479

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.000493

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0185 AC: 26993 AN: 1460360 Hom.: 528 Cov.: 32 AF XY: 0.0179 AC XY: 13006 AN XY: 726472

Gnomad4 AFR exome AF: 0.0688

Gnomad4 AMR exome AF: 0.0483

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0348 AC: 5285 AN: 151722 Hom.: 162 Cov.: 31 AF XY: 0.0331 AC XY: 2455 AN XY: 74154

Gnomad4 AFR AF: 0.0674

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00376

Gnomad4 FIN AF: 0.00152

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0579

Alfa AF: 0.0265 Hom.: 192

Bravo AF: 0.0406

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.0685 AC: 207

ESP6500EA AF: 0.0212 AC: 115

ExAC AF: 0.0232 AC: 2739

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0231

EpiControl AF: 0.0239

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MSH5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.059	T;T;.;.;.
Eigen	Benign	-0.080
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;L;L
PROVEAN	Benign	2.5	N;N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.90	T;T;T;T;T
Sift4G	Benign	0.35	T;T;D;T;T
Polyphen		0.013	B;B;.;B;B
Vest4		0.11
MPC		0.51
ClinPred		0.018	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.40

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: rs28381349; hg19: chr6-31709045;