rs1478834

Variant names:

• chr5-80653756-C-A
• rs1478834
• NM_000791.4:c.136+252G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000791.4(DHFR):​c.136+252G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,012 control chromosomes in the GnomAD database, including 5,098 homozygotes. 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 0.25 (5098 hom., cov: 32)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFR	NM_000791.4	c.136+252G>T		intron_variant	Intron 2 of 5	ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.-21+648G>T		intron_variant	Intron 1 of 4		NP_001277283.1
DHFR	NM_001290357.2	c.136+252G>T		intron_variant	Intron 2 of 4		NP_001277286.1
DHFR	NR_110936.2	n.580+648G>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.136+252G>T		intron_variant	Intron 2 of 5	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38640 AN: 151890 Hom.: 5091 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.283

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.254 AC: 38670 AN: 152012 Hom.: 5098 Cov.: 32 AF XY: 0.252 AC XY: 18695 AN XY: 74322

African (AFR) AF: 0.280 AC: 11607 AN: 41446

American (AMR) AF: 0.229 AC: 3506 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1008 AN: 3468

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

South Asian (SAS) AF: 0.317 AC: 1529 AN: 4830

European-Finnish (FIN) AF: 0.181 AC: 1911 AN: 10552

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 17980 AN: 67940

Other (OTH) AF: 0.282 AC: 594 AN: 2110

Alfa AF: 0.270 Hom.: 7298

Bravo AF: 0.256

Asia WGS AF: 0.204 AC: 713 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.27
DANN	Benign	0.53
PhyloP100		-1.4
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: rs1478834; hg19: chr5-79949575;