rs13161245

Positions:

• chr5-80648914-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.558

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHFR	NM_000791.4	c.242+475T>C		intron_variant		ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.86+475T>C		intron_variant			NP_001277283.1
DHFR	NM_001290357.2	c.242+475T>C		intron_variant			NP_001277286.1
DHFR	NR_110936.2	n.686+475T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.242+475T>C		intron_variant		1	NM_000791.4	ENSP00000396308	P1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38623 AN: 151980 Hom.: 5124 Cov.: 32

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: 12 AN: 92 Hom.: 0 Cov.: 0 AF XY: 0.173 AC XY: 9 AN XY: 52

Gnomad4 AMR exome AF: 0.200

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.250

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.254 AC: 38650 AN: 152098 Hom.: 5130 Cov.: 32 AF XY: 0.251 AC XY: 18673 AN XY: 74384

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0400

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.282

Alfa AF: 0.269 Hom.: 2637

Bravo AF: 0.255

Asia WGS AF: 0.205 AC: 714 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.5
DANN	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs13161245; hg19: chr5-79944733;