rs3045983

Positions:

• chr5-80654922-GCCCCCAGCT-G
• chr5-80654922-GCCCCCAGCT-GCCCCCAGCTCCCCCAGCT

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_002439.5(MSH3):​c.199_207delCCAGCTCCC​(p.Pro67_Pro69del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,521,560 control chromosomes in the GnomAD database, including 63,065 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5185 hom., cov: 0)
  • Exomes 𝑓: 0.27 (57880 hom.)
• Consequence: MSH3 NM_002439.5 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0640

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.

• PM4: Nonframeshift variant in NON repetitive region in NM_002439.5.
• BP6: Variant 5-80654922-GCCCCCAGCT-G is Benign according to our data. Variant chr5-80654922-GCCCCCAGCT-G is described in ClinVar as [Benign]. Clinvar id is 402590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80654922-GCCCCCAGCT-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH3	NM_002439.5	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	1/24	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-442_-434delAGCTGGGGG		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	ENST00000265081.7	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	1/24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000667069.1	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	1/22			ENSP00000499502.1
DHFR	ENST00000439211.7	c.-442_-434delAGCTGGGGG		5_prime_UTR_variant	1/6	1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000670357.1	n.199_207delCCAGCTCCC		non_coding_transcript_exon_variant	1/25			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 38926 AN: 150902 Hom.: 5181 Cov.: 0

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0474

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.287

GnomAD3 exomes AF: 0.309 AC: 39028 AN: 126454 Hom.: 7452 AF XY: 0.318 AC XY: 22606 AN XY: 71060

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.0633

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.272 AC: 373255 AN: 1370550 Hom.: 57880 AF XY: 0.276 AC XY: 187394 AN XY: 678858

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.0379

Gnomad4 SAS exome AF: 0.353

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.258 AC: 38939 AN: 151010 Hom.: 5185 Cov.: 0 AF XY: 0.256 AC XY: 18875 AN XY: 73796

Gnomad4 AFR AF: 0.281

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.0474

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.285

Alfa AF: 0.138 Hom.: 557

Asia WGS AF: 0.210 AC: 730 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Constitutional megaloblastic anemia with severe neurologic disease Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2021

This variant is associated with the following publications: (PMID: 25927356) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3045983; hg19: chr5-79950741;