rs1677694

Variant names:

• chr5-80640478-G-A
• rs1677694
• NM_000791.4:c.243-2469C>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.243-2469C>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 152,040 control chromosomes in the GnomAD database, including 5,127 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 (5127 hom., cov: 32)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.762
• Publications: 9 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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

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.243-2469C>T		intron	N/A	NP_000782.1	P00374-1
	DHFR	NM_001290354.2		c.87-2469C>T		intron	N/A	NP_001277283.1	P00374-2
	DHFR	NM_001290357.2		c.243-2469C>T		intron	N/A	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.243-2469C>T		intron	N/A	ENSP00000396308.2	P00374-1
	DHFR	ENST00000513048.5	TSL:1	n.251-6486C>T		intron	N/A
	DHFR	ENST00000505337.5	TSL:2	c.243-2469C>T		intron	N/A	ENSP00000426474.1	P00374-1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38622 AN: 151922 Hom.: 5121 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.229

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: 0.284

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

GnomAD4 genome AF: 0.254 AC: 38649 AN: 152040 Hom.: 5127 Cov.: 32 AF XY: 0.251 AC XY: 18674 AN XY: 74320

African (AFR) AF: 0.278 AC: 11528 AN: 41462

American (AMR) AF: 0.229 AC: 3498 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3470

East Asian (EAS) AF: 0.0398 AC: 206 AN: 5178

South Asian (SAS) AF: 0.317 AC: 1530 AN: 4822

European-Finnish (FIN) AF: 0.182 AC: 1917 AN: 10548

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

European-Non Finnish (NFE) AF: 0.265 AC: 18034 AN: 67984

Other (OTH) AF: 0.283 AC: 596 AN: 2108

Alfa AF: 0.260 Hom.: 852

Bravo AF: 0.255

Asia WGS AF: 0.205 AC: 714 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.76
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1677694;

hg19: chr5-79936297;