5-80633921-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000791.4(DHFR):c.441G>A(p.Thr147=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,612,738 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: DHFR NM_000791.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.12

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-80633921-C-T is Benign according to our data. Variant chr5-80633921-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 723950.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHFR	NM_000791.4	c.441G>A	p.Thr147=	synonymous_variant	5/6	ENST00000439211.7
DHFR	NM_001290354.2	c.285G>A	p.Thr95=	synonymous_variant	4/5
DHFR	NM_001290357.2	c.369+3962G>A		intron_variant
DHFR	NR_110936.2	n.758G>A		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHFR	ENST00000439211.7	c.441G>A	p.Thr147=	synonymous_variant	5/6	1	NM_000791.4	P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152094 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000656 AC: 164 AN: 249976 Hom.: 0 AF XY: 0.000701 AC XY: 95 AN XY: 135584

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000848

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000797 AC: 1164 AN: 1460526 Hom.: 2 Cov.: 30 AF XY: 0.000787 AC XY: 572 AN XY: 726582

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.000846

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000390 AC XY: 29 AN XY: 74426

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000461

EpiCase AF: 0.000601

EpiControl AF: 0.000948

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.1
Dann	Benign	0.61

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: rs201959090; hg19: chr5-79929740;