5-80655040-G-T

Variant names:

• chr5-80655040-G-T
• rs1677658
• NM_002439.5:c.237+76G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002439.5(MSH3):​c.237+76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 867,144 control chromosomes in the GnomAD database, including 10,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1211 hom., cov: 30)
  • Exomes 𝑓: 0.15 (9518 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510
• Publications: 11 publications found

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

DHFR Gene-Disease associations (from GenCC):

• constitutional megaloblastic anemia with severe neurologic disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-80655040-G-T is Benign according to our data. Variant chr5-80655040-G-T is described in ClinVar as [Benign]. Clinvar id is 1261132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.237+76G>T		intron_variant	Intron 1 of 23	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-551C>A		upstream_gene_variant		ENST00000439211.7	NP_000782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.237+76G>T		intron_variant	Intron 1 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000667069.1	c.237+76G>T		intron_variant	Intron 1 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.237+76G>T		intron_variant	Intron 1 of 24			ENSP00000499791.1
DHFR	ENST00000439211.7	c.-551C>A		upstream_gene_variant		1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000658259.1	c.-154G>T		upstream_gene_variant				ENSP00000499617.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17873 AN: 151624 Hom.: 1211 Cov.: 30

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.000976

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.146 AC: 104802 AN: 715412 Hom.: 9518 Cov.: 10 AF XY: 0.149 AC XY: 53990 AN XY: 362548

African (AFR) AF: 0.0656 AC: 908 AN: 13836

American (AMR) AF: 0.164 AC: 1996 AN: 12170

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 2541 AN: 13814

East Asian (EAS) AF: 0.000492 AC: 13 AN: 26430

South Asian (SAS) AF: 0.148 AC: 6553 AN: 44240

European-Finnish (FIN) AF: 0.123 AC: 3635 AN: 29622

Middle Eastern (MID) AF: 0.224 AC: 543 AN: 2420

European-Non Finnish (NFE) AF: 0.155 AC: 83603 AN: 539078

Other (OTH) AF: 0.148 AC: 5010 AN: 33802

GnomAD4 genome AF: 0.118 AC: 17865 AN: 151732 Hom.: 1211 Cov.: 30 AF XY: 0.116 AC XY: 8584 AN XY: 74154

African (AFR) AF: 0.0569 AC: 2359 AN: 41426

American (AMR) AF: 0.125 AC: 1907 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3464

East Asian (EAS) AF: 0.000979 AC: 5 AN: 5108

South Asian (SAS) AF: 0.131 AC: 632 AN: 4808

European-Finnish (FIN) AF: 0.113 AC: 1195 AN: 10534

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10607 AN: 67820

Other (OTH) AF: 0.139 AC: 292 AN: 2102

Alfa AF: 0.129 Hom.: 156

Bravo AF: 0.116

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.2
DANN	Benign	0.94
PhyloP100		-0.051
PromoterAI		-0.035	Neutral
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: rs1677658; hg19: chr5-79950859;