5-80654689-C-G

Variant names:

• chr5-80654689-C-G
• rs1105525
• NM_002439.5:c.-39C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002439.5(MSH3):​c.-39C>G 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 0.0000032 in 1,561,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MSH3 NM_002439.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800
• Publications: 20 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.-39C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	NP_002430.3	P20585
	MSH3	NM_002439.5	MANE Select	c.-39C>G		5_prime_UTR	Exon 1 of 24	NP_002430.3	P20585
	DHFR	NM_000791.4	MANE Select	c.-200G>C		5_prime_UTR	Exon 1 of 6	NP_000782.1	P00374-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.-39C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000265081.6	P20585
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.-39C>G		5_prime_UTR	Exon 1 of 24	ENSP00000265081.6	P20585
	DHFR	ENST00000439211.7	TSL:1 MANE Select	c.-200G>C		5_prime_UTR	Exon 1 of 6	ENSP00000396308.2	P00374-1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151488 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000509 AC: 1 AN: 196436 AF XY: 0.00

Gnomad AFR exome AF: 0.000120

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 7.09e-7 AC: 1 AN: 1410328 Hom.: 0 Cov.: 26 AF XY: 0.00000142 AC XY: 1 AN XY: 702454

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000340 AC: 1 AN: 29450

American (AMR) AF: 0.00 AC: 0 AN: 41336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24928

East Asian (EAS) AF: 0.00 AC: 0 AN: 35296

South Asian (SAS) AF: 0.00 AC: 0 AN: 83354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086436

Other (OTH) AF: 0.00 AC: 0 AN: 58284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151488 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73942

African (AFR) AF: 0.0000968 AC: 4 AN: 41324

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67766

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.54
PhyloP100		-0.0080
PromoterAI		-0.045	Neutral

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: rs1105525; hg19: chr5-79950508;