rs1643649

Variant names:

• chr5-80643630-T-C
• rs1643649
• NM_000791.4:c.243-5621A>G

Variant summary

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

The NM_000791.4(DHFR):​c.243-5621A>G 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 152,064 control chromosomes in the GnomAD database, including 5,124 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 (5124 hom., cov: 32)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.634
• Publications: 10 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=-1.01).
• 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.243-5621A>G		intron_variant	Intron 3 of 5	ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.87-5621A>G		intron_variant	Intron 2 of 4		NP_001277283.1
DHFR	NM_001290357.2	c.243-5621A>G		intron_variant	Intron 3 of 4		NP_001277286.1
DHFR	NR_110936.2	n.686+5759A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.243-5621A>G		intron_variant	Intron 3 of 5	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38619 AN: 151944 Hom.: 5118 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.254 AC: 38646 AN: 152064 Hom.: 5124 Cov.: 32 AF XY: 0.251 AC XY: 18656 AN XY: 74306

African (AFR) AF: 0.278 AC: 11527 AN: 41470

American (AMR) AF: 0.229 AC: 3501 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3466

East Asian (EAS) AF: 0.0401 AC: 208 AN: 5186

South Asian (SAS) AF: 0.317 AC: 1525 AN: 4810

European-Finnish (FIN) AF: 0.182 AC: 1918 AN: 10564

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

European-Non Finnish (NFE) AF: 0.265 AC: 18030 AN: 67968

Other (OTH) AF: 0.282 AC: 595 AN: 2110

Alfa AF: 0.180 Hom.: 458

Bravo AF: 0.255

Asia WGS AF: 0.205 AC: 714 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.38
PhyloP100		-0.63
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: rs1643649; hg19: chr5-79939449;