dbSNP rs13161245: DHFR:c.242+475T>C (chr5-80648914-A-G) – 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.242+475T>C 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 152,190 control chromosomes in the GnomAD database, including 5,130 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 ( 5130 hom., cov: 32)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

DHFR
NM_000791.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.558

Publications

17 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=-0.88).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DHFR	NM_000791.4	MANE Select	c.242+475T>C	intron	N/A	NP_000782.1
DHFR	NM_001290354.2		c.86+475T>C	intron	N/A	NP_001277283.1
DHFR	NM_001290357.2		c.242+475T>C	intron	N/A	NP_001277286.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DHFR	ENST00000439211.7	TSL:1 MANE Select	c.242+475T>C	intron	N/A	ENSP00000396308.2
DHFR	ENST00000513048.5	TSL:1	n.250+475T>C	intron	N/A
DHFR	ENST00000505337.5	TSL:2	c.242+475T>C	intron	N/A	ENSP00000426474.1

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38623

AN:

151980

Hom.:

5124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.278

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.230

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:

0.130

AC:

AN:

Hom.:

Cov.:

AF XY:

0.173

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.200

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.111

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.254

AC:

38650

AN:

152098

Hom.:

5130

Cov.:

AF XY:

0.251

AC XY:

18673

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.278

AC:

11523

AN:

41474

American (AMR)

AF:

0.229

AC:

3501

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1010

AN:

3472

East Asian (EAS)

AF:

0.0400

AC:

207

AN:

5178

South Asian (SAS)

AF:

0.317

AC:

1530

AN:

4824

European-Finnish (FIN)

AF:

0.182

AC:

1926

AN:

10582

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.265

AC:

18026

AN:

67980

Other (OTH)

AF:

0.282

AC:

597

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1485

2970

4454

5939

7424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.268

Hom.:

2952

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

-0.88

CADD

Benign

4.5

(source)

DANN

Benign

0.81

PhyloP100

-0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over