rs12109877

Variant names:

• chr5-80625997-A-T
• rs12109877
• NM_000791.4:c.*3090T>A

Variant summary

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

The NM_000791.4(DHFR):​c.*3090T>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 152,286 control chromosomes in the GnomAD database, including 688 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 0.058 (688 hom., cov: 32)
• Consequence: DHFR NM_000791.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFR	NM_000791.4	c.*3090T>A		downstream_gene_variant		ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.*3090T>A		downstream_gene_variant			NP_001277283.1
DHFR	NM_001290357.2	c.*3148T>A		downstream_gene_variant			NP_001277286.1
DHFR	NR_110936.2	n.*229T>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.*3090T>A		downstream_gene_variant		1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8768 AN: 152168 Hom.: 688 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.0445

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

GnomAD4 genome AF: 0.0578 AC: 8805 AN: 152286 Hom.: 688 Cov.: 32 AF XY: 0.0556 AC XY: 4139 AN XY: 74474

African (AFR) AF: 0.181 AC: 7523 AN: 41514

American (AMR) AF: 0.0239 AC: 365 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4830

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10626

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00789 AC: 537 AN: 68036

Other (OTH) AF: 0.0464 AC: 98 AN: 2112

Alfa AF: 0.0383 Hom.: 44

Bravo AF: 0.0640

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.44
PhyloP100		1.4

Splicing

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

Other links and lift over

dbSNP: rs12109877; hg19: chr5-79921816;