5-80654689-C-T

Position:

• chr5-80654689-C-T

Variant summary

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

The NM_002439.5(MSH3):​c.-39C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,560,524 control chromosomes in the GnomAD database, including 23,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1639 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21775 hom.)
• Consequence: MSH3 NM_002439.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00800

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-80654689-C-T is Benign according to our data. Variant chr5-80654689-C-T is described in ClinVar as [Benign]. Clinvar id is 1220684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH3	NM_002439.5	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	1/24	ENST00000265081.7	NP_002430.3
MSH3	NM_002439.5	c.-39C>T		5_prime_UTR_variant	1/24	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-200G>A		5_prime_UTR_variant	1/6	ENST00000439211.7	NP_000782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	1/24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000265081	c.-39C>T		5_prime_UTR_variant	1/24	1	NM_002439.5	ENSP00000265081.6
DHFR	ENST00000439211.7	c.-200G>A		5_prime_UTR_variant	1/6	1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000670357.1	n.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	1/25			ENSP00000499791.1
MSH3	ENST00000670357.1	n.-39C>T		non_coding_transcript_exon_variant	1/25			ENSP00000499791.1
MSH3	ENST00000670357.1	n.-39C>T		5_prime_UTR_variant	1/25			ENSP00000499791.1
MSH3	ENST00000667069.1	c.-39C>T		upstream_gene_variant				ENSP00000499502.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20264 AN: 151422 Hom.: 1639 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.156 AC: 30664 AN: 196436 Hom.: 2865 AF XY: 0.166 AC XY: 18324 AN XY: 110392

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.0686

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.169 AC: 238344 AN: 1408996 Hom.: 21775 Cov.: 26 AF XY: 0.172 AC XY: 120785 AN XY: 701824

Gnomad4 AFR exome AF: 0.0413

Gnomad4 AMR exome AF: 0.0844

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.0672

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.134 AC: 20272 AN: 151528 Hom.: 1639 Cov.: 32 AF XY: 0.136 AC XY: 10053 AN XY: 74026

Gnomad4 AFR AF: 0.0478

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.0677

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.112

Alfa AF: 0.104 Hom.: 291

Bravo AF: 0.117

Asia WGS AF: 0.134 AC: 463 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.2
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1105525; hg19: chr5-79950508; COSMIC: COSV54143671; COSMIC: COSV54143671;