chr5-80649892-C-A

Variant names:

• chr5-80649892-C-A
• rs836821
• NM_000791.4:c.137-398G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000791.4(DHFR):​c.137-398G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 679,908 control chromosomes in the GnomAD database, including 23,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5125 hom., cov: 32)
  • Exomes 𝑓: 0.25 (18241 hom.)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.75
• Publications: 8 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 5-80649892-C-A is Benign according to our data. Variant chr5-80649892-C-A is described in ClinVar as [Benign]. Clinvar id is 3910468.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 rank	MANE	Protein	UniProt
DHFR	NM_000791.4	c.137-398G>T		intron_variant	Intron 2 of 5	ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.-20-398G>T		intron_variant	Intron 1 of 4		NP_001277283.1
DHFR	NM_001290357.2	c.137-398G>T		intron_variant	Intron 2 of 4		NP_001277286.1
DHFR	NR_110936.2	n.581-398G>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.137-398G>T		intron_variant	Intron 2 of 5	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38625 AN: 151992 Hom.: 5119 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.251 AC: 132236 AN: 527798 Hom.: 18241 AF XY: 0.255 AC XY: 71589 AN XY: 280198

African (AFR) AF: 0.277 AC: 3988 AN: 14394

American (AMR) AF: 0.174 AC: 4621 AN: 26568

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 4348 AN: 16242

East Asian (EAS) AF: 0.0216 AC: 680 AN: 31432

South Asian (SAS) AF: 0.329 AC: 17241 AN: 52364

European-Finnish (FIN) AF: 0.187 AC: 5809 AN: 31060

Middle Eastern (MID) AF: 0.437 AC: 1661 AN: 3800

European-Non Finnish (NFE) AF: 0.267 AC: 86207 AN: 322970

Other (OTH) AF: 0.265 AC: 7681 AN: 28968

GnomAD4 genome AF: 0.254 AC: 38652 AN: 152110 Hom.: 5125 Cov.: 32 AF XY: 0.251 AC XY: 18673 AN XY: 74364

African (AFR) AF: 0.278 AC: 11525 AN: 41476

American (AMR) AF: 0.229 AC: 3505 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3472

East Asian (EAS) AF: 0.0398 AC: 206 AN: 5180

South Asian (SAS) AF: 0.317 AC: 1529 AN: 4820

European-Finnish (FIN) AF: 0.182 AC: 1922 AN: 10572

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18029 AN: 67994

Other (OTH) AF: 0.283 AC: 596 AN: 2106

Alfa AF: 0.127 Hom.: 198

Bravo AF: 0.255

Asia WGS AF: 0.205 AC: 714 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.82
DANN	Benign	0.54
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs836821; hg19: chr5-79945711;