chr5-80629141-G-C

Variant names:

• chr5-80629141-G-C
• NM_000791.4:c.510C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000791.4(DHFR):​c.510C>G​(p.Val170Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DHFR NM_000791.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.364
• Publications: 0 publications found

Genes affected

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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-80629141-G-C is Benign according to our data. Variant chr5-80629141-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3675644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.364 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000791.4. 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
	DHFR	NM_000791.4	MANE Select	c.510C>G	p.Val170Val	synonymous	Exon 6 of 6	NP_000782.1	P00374-1
	DHFR	NM_001290354.2		c.354C>G	p.Val118Val	synonymous	Exon 5 of 5	NP_001277283.1	P00374-2
	DHFR	NM_001290357.2		c.*4C>G		3_prime_UTR	Exon 5 of 5	NP_001277286.1	B4DM58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHFR	ENST00000439211.7	TSL:1 MANE Select	c.510C>G	p.Val170Val	synonymous	Exon 6 of 6	ENSP00000396308.2	P00374-1
	DHFR	ENST00000513048.5	TSL:1	n.391C>G		non_coding_transcript_exon	Exon 4 of 4
	DHFR	ENST00000505337.5	TSL:2	c.510C>G	p.Val170Val	synonymous	Exon 6 of 7	ENSP00000426474.1	P00374-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419674 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 708364

African (AFR) AF: 0.00 AC: 0 AN: 32478

American (AMR) AF: 0.00 AC: 0 AN: 43804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 83134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077590

Other (OTH) AF: 0.00 AC: 0 AN: 58948

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.8
DANN	Benign	0.78
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr5-79924960;