1-97573881-C-T

Position:

• chr1-97573881-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000110.4(DPYD):​c.1218G>A​(p.Met406Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,662 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (98 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (87 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: 3.71

Genes affected

DPYD (HGNC:3012): (dihydropyrimidine dehydrogenase) The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027598143).
• BP6: Variant 1-97573881-C-T is Benign according to our data. Variant chr1-97573881-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100101.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Benign=4}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1218G>A	p.Met406Ile	missense_variant	11/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1218G>A	p.Met406Ile	missense_variant	11/23	1	NM_000110.4	ENSP00000359211.3

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3080 AN: 152052 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00879

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00501 AC: 1259 AN: 251118 Hom.: 29 AF XY: 0.00365 AC XY: 495 AN XY: 135698

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00221 AC: 3235 AN: 1461492 Hom.: 87 Cov.: 31 AF XY: 0.00194 AC XY: 1407 AN XY: 727044

Gnomad4 AFR exome AF: 0.0718

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.00604

GnomAD4 genome AF: 0.0204 AC: 3104 AN: 152170 Hom.: 98 Cov.: 32 AF XY: 0.0200 AC XY: 1491 AN XY: 74396

Gnomad4 AFR AF: 0.0700

Gnomad4 AMR AF: 0.00878

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00490 Hom.: 49

Bravo AF: 0.0229

ESP6500AA AF: 0.0576 AC: 254

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00605 AC: 734

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 08, 2017	- -
not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -

Dihydropyrimidine dehydrogenase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 22, 2021

Variant summary: DPYD c.1218G>A (p.Met406Ile) results in a conservative amino acid change located in the FAD/NAD(P)-binding domain (IPR023753) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 251118 control chromosomes, predominantly at a frequency of 0.065 within the African or African-American subpopulation in the gnomAD database, including 29 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 26 fold of the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1218G>A in individuals affected with Dihydropyrimidine Dehydrogenase Deficiency has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on DPYD enzyme activity (example, Offer_2014, subsequently cited by Hishinuma_2020). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign, n=2). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.33
Sift	Benign	0.46	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.51		Loss of sheet (P = 0.0181);
MVP		0.88
MPC		0.060
ClinPred		0.011	T
GERP RS		5.8
Varity_R		0.51
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61622928; hg19: chr1-98039437;