chr5-80654731-T-A

Position:

• chr5-80654731-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002439.5(MSH3):​c.4T>A​(p.Ser2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH3 NM_002439.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24874789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5	c.4T>A	p.Ser2Thr	missense_variant	1/24	ENST00000265081.7
DHFR	NM_000791.4	c.-242A>T		5_prime_UTR_variant	1/6	ENST00000439211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.4T>A	p.Ser2Thr	missense_variant	1/24	1	NM_002439.5	P2
DHFR	ENST00000439211.7	c.-242A>T		5_prime_UTR_variant	1/6	1	NM_000791.4	P1
MSH3	ENST00000667069.1	c.4T>A	p.Ser2Thr	missense_variant	1/22
MSH3	ENST00000670357.1	c.4T>A	p.Ser2Thr	missense_variant, NMD_transcript_variant	1/25

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Endometrial carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.17
Sift	Benign	0.036	D
Sift4G	Benign	0.57	T
Polyphen		0.32	B
Vest4		0.29
MutPred		0.19		Gain of glycosylation at S2 (P = 0.1102);
MVP		0.58
MPC		0.031
ClinPred		0.13	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-79950550;