Variant chr5-80654922-G-GCCCCCAGCT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_002439.5(MSH3):c.199_207dupCCAGCTCCC(p.Pro67_Pro69dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

MSH3
NM_002439.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0550

Variant links:

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]

MSH3 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_002439.5.

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5 link	c.199_207dupCCAGCTCCC	p.Pro67_Pro69dup	conservative_inframe_insertion	Exon 1 of 24	ENST00000265081.7	NP_002430.3	P20585
DHFR	NM_000791.4 link	c.-442_-434dupAGCTGGGGG		5_prime_UTR_variant	Exon 1 of 6	ENST00000439211.7	NP_000782.1	P00374-1B0YJ76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 link	c.199_207dupCCAGCTCCC	p.Pro67_Pro69dup	conservative_inframe_insertion	Exon 1 of 24	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000667069.1 link	c.199_207dupCCAGCTCCC	p.Pro67_Pro69dup	conservative_inframe_insertion	Exon 1 of 22			ENSP00000499502.1	A0A590UJN8
DHFR	ENST00000439211.7 link	c.-442_-434dupAGCTGGGGG		5_prime_UTR_variant	Exon 1 of 6	1	NM_000791.4	ENSP00000396308.2	P00374-1
MSH3	ENST00000670357.1 link	n.199_207dupCCAGCTCCC		non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000237

AC:

AN:

126454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

71060

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000167

AC:

AN:

1380954

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

683602

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.0000526

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4

Uncertain:1

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over