20-18596149-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080820.6(DTD1):c.278T>G(p.Phe93Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTD1 NM_080820.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

DTD1 (HGNC:16219): (D-aminoacyl-tRNA deacylase 1) The protein encoded by this gene is similar in sequence to histidyl-tRNA synthetase, which hydrolyzes D-tyrosyl-tRNA(Tyr) into D-tyrosine and free tRNA(Tyr). The encoded protein binds the DNA unwinding element and plays a role in the initiation of DNA replication. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTD1	NM_080820.6	c.278T>G	p.Phe93Cys	missense_variant	3/6	ENST00000377452.4
DTD1	NM_001318043.2	c.278T>G	p.Phe93Cys	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTD1	ENST00000377452.4	c.278T>G	p.Phe93Cys	missense_variant	3/6	1	NM_080820.6	P1
DTD1	ENST00000494921.2	c.278T>G	p.Phe93Cys	missense_variant	3/5	2
DTD1	ENST00000647441.1	c.278T>G	p.Phe93Cys	missense_variant, NMD_transcript_variant	3/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.278T>G (p.F93C) alteration is located in exon 3 (coding exon 3) of the DTD1 gene. This alteration results from a T to G substitution at nucleotide position 278, causing the phenylalanine (F) at amino acid position 93 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.45	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.63
MutPred		0.94		.;Loss of stability (P = 0.1101);Loss of stability (P = 0.1101);
MVP		0.48
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-18576793;