chr5-80654344-C-CTGGCGCGTCCCGCCCAGGT

Variant names:

• chr5-80654344-C-CTGGCGCGTCCCGCCCAGGT
• rs70991108
• NM_000791.4:c.86+59_86+60insACCTGGGCGGGACGCGCCA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000791.4(DHFR):​c.86+59_86+60insACCTGGGCGGGACGCGCCA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,562,068 control chromosomes in the GnomAD database, including 240,659 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20790 hom., cov: 0)
  • Exomes 𝑓: 0.55 (219869 hom.)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -0.762
• Publications: 47 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 -16 ACMG points.

• BP6: Variant 5-80654344-C-CTGGCGCGTCCCGCCCAGGT is Benign according to our data. Variant chr5-80654344-C-CTGGCGCGTCCCGCCCAGGT is described in ClinVar as Benign. ClinVar VariationId is 157590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFR	NM_000791.4	c.86+59_86+60insACCTGGGCGGGACGCGCCA		intron_variant	Intron 1 of 5	ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.-21+59_-21+60insACCTGGGCGGGACGCGCCA		intron_variant	Intron 1 of 4		NP_001277283.1
DHFR	NM_001290357.2	c.86+59_86+60insACCTGGGCGGGACGCGCCA		intron_variant	Intron 1 of 4		NP_001277286.1
DHFR	NR_110936.2	n.580+59_580+60insACCTGGGCGGGACGCGCCA		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.86+59_86+60insACCTGGGCGGGACGCGCCA		intron_variant	Intron 1 of 5	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78884 AN: 151926 Hom.: 20781 Cov.: 0

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.545

GnomAD4 exome AF: 0.555 AC: 782250 AN: 1410024 Hom.: 219869 AF XY: 0.560 AC XY: 393444 AN XY: 702570

African (AFR) AF: 0.440 AC: 14285 AN: 32440

American (AMR) AF: 0.413 AC: 18097 AN: 43858

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 14287 AN: 25556

East Asian (EAS) AF: 0.340 AC: 13363 AN: 39328

South Asian (SAS) AF: 0.666 AC: 56303 AN: 84546

European-Finnish (FIN) AF: 0.520 AC: 26986 AN: 51922

Middle Eastern (MID) AF: 0.671 AC: 2745 AN: 4088

European-Non Finnish (NFE) AF: 0.564 AC: 603762 AN: 1069830

Other (OTH) AF: 0.555 AC: 32422 AN: 58456

GnomAD4 genome AF: 0.519 AC: 78943 AN: 152044 Hom.: 20790 Cov.: 0 AF XY: 0.520 AC XY: 38654 AN XY: 74316

African (AFR) AF: 0.445 AC: 18433 AN: 41468

American (AMR) AF: 0.501 AC: 7665 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1993 AN: 3472

East Asian (EAS) AF: 0.375 AC: 1933 AN: 5156

South Asian (SAS) AF: 0.663 AC: 3201 AN: 4828

European-Finnish (FIN) AF: 0.526 AC: 5559 AN: 10574

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38415 AN: 67940

Other (OTH) AF: 0.544 AC: 1148 AN: 2110

Alfa AF: 0.332 Hom.: 595

Asia WGS AF: 0.538 AC: 1873 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29147684) -

Gastrointestinal stromal tumor Uncertain:1

-

Department of Pharmacy and Biotechnology, University of Bologna

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.76
Mutation Taster		=14/86	disease causing

Splicing

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

Other links and lift over

dbSNP: rs70991108; hg19: chr5-79950163;