rs7387

Variant names:

• chr5-80628972-T-A
• rs7387
• ENST00000513048.5:n.560A>T

Variant summary

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

The ENST00000513048.5(DHFR):​n.560A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 585,468 control chromosomes in the GnomAD database, including 19,691 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 (5120 hom., cov: 30)
  • Exomes 𝑓: 0.25 (14571 hom.)
• Consequence: DHFR ENST00000513048.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.254
• Publications: 17 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=-0.95).
• 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.*115A>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000439211.7	NP_000782.1
DHFR	NR_110936.2	n.996A>T		non_coding_transcript_exon_variant	Exon 4 of 4
DHFR	NM_001290354.2	c.*115A>T		3_prime_UTR_variant	Exon 5 of 5		NP_001277283.1
DHFR	NM_001290357.2	c.*173A>T		3_prime_UTR_variant	Exon 5 of 5		NP_001277286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.*115A>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38560 AN: 151784 Hom.: 5114 Cov.: 30

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0399

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

GnomAD4 exome AF: 0.246 AC: 106652 AN: 433566 Hom.: 14571 Cov.: 5 AF XY: 0.251 AC XY: 57407 AN XY: 229116

African (AFR) AF: 0.279 AC: 3273 AN: 11718

American (AMR) AF: 0.187 AC: 3169 AN: 16902

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 3447 AN: 12798

East Asian (EAS) AF: 0.0214 AC: 622 AN: 29094

South Asian (SAS) AF: 0.327 AC: 12902 AN: 39496

European-Finnish (FIN) AF: 0.183 AC: 7200 AN: 39420

Middle Eastern (MID) AF: 0.386 AC: 693 AN: 1796

European-Non Finnish (NFE) AF: 0.267 AC: 68945 AN: 257976

Other (OTH) AF: 0.263 AC: 6401 AN: 24366

GnomAD4 genome AF: 0.254 AC: 38587 AN: 151902 Hom.: 5120 Cov.: 30 AF XY: 0.251 AC XY: 18636 AN XY: 74256

African (AFR) AF: 0.277 AC: 11481 AN: 41374

American (AMR) AF: 0.229 AC: 3495 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1009 AN: 3470

East Asian (EAS) AF: 0.0400 AC: 206 AN: 5152

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

European-Finnish (FIN) AF: 0.182 AC: 1919 AN: 10566

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

European-Non Finnish (NFE) AF: 0.265 AC: 18025 AN: 67962

Other (OTH) AF: 0.282 AC: 594 AN: 2106

Alfa AF: 0.253 Hom.: 580

Bravo AF: 0.255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	9.4
DANN	Benign	0.68
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs7387; hg19: chr5-79924791;