Genetic Variant DHFR:c.*2876G>A (chr5-80626211-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000791.4(DHFR):c.*2876G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 201,964 control chromosomes in the GnomAD database, including 1,702 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 0.12 ( 1219 hom., cov: 29)

Exomes 𝑓: 0.12 ( 483 hom. )

Consequence

DHFR
NM_000791.4 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.770

Publications

22 publications found

Variant links:

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

DHFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
DHFR	NM_000791.4 link	c.*2876G>A	downstream_gene_variant	ENST00000439211.7	NP_000782.1	P00374-1B0YJ76
DHFR	NM_001290354.2 link	c.*2876G>A	downstream_gene_variant		NP_001277283.1	P00374-2
DHFR	NM_001290357.2 link	c.*2934G>A	downstream_gene_variant		NP_001277286.1	B4DM58
DHFR	NR_110936.2 link	n.*15G>A	downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7 link	c.*2876G>A		downstream_gene_variant		1	NM_000791.4	ENSP00000396308.2		P00374-1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18029

AN:

152042

Hom.:

1219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0583

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.141

GnomAD4 exome

AF:

0.124

AC:

6190

AN:

49804

Hom.:

483

Cov.:

AF XY:

0.126

AC XY:

2918

AN XY:

23102

show subpopulations

African (AFR)

AF:

0.0561

AC:

121

AN:

2158

American (AMR)

AF:

0.101

AC:

139

AN:

1372

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

516

AN:

3218

East Asian (EAS)

AF:

0.000123

AC:

AN:

8124

South Asian (SAS)

AF:

0.139

AC:

AN:

446

European-Finnish (FIN)

AF:

0.0556

AC:

AN:

Middle Eastern (MID)

AF:

0.185

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.157

AC:

4708

AN:

30068

Other (OTH)

AF:

0.143

AC:

586

AN:

4084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

235

470

704

939

1174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.118

AC:

18024

AN:

152160

Hom.:

1219

Cov.:

AF XY:

0.117

AC XY:

8680

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0583

AC:

2419

AN:

41510

American (AMR)

AF:

0.125

AC:

1914

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

665

AN:

3466

East Asian (EAS)

AF:

0.000964

AC:

AN:

5186

South Asian (SAS)

AF:

0.132

AC:

636

AN:

4822

European-Finnish (FIN)

AF:

0.115

AC:

1219

AN:

10578

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10667

AN:

68008

Other (OTH)

AF:

0.139

AC:

293

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

797

1594

2392

3189

3986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.146

Hom.:

4808

Bravo

AF:

0.117

Asia WGS

AF:

0.0710

AC:

249

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.49

(source)

DANN

Benign

0.41

PhyloP100

-0.77

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over