4-36284291-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170700.3(DTHD1):c.587C>T(p.Ser196Leu) 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 benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTHD1 NM_001170700.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.871

Genes affected

DTHD1 (HGNC:37261): (death domain containing 1) This gene encodes a protein which contains a death domain. Death domain-containing proteins function in signaling pathways and formation of signaling complexes, as well as the apoptosis pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089286834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTHD1	NM_001170700.3	c.587C>T	p.Ser196Leu	missense_variant	2/10	ENST00000639862.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTHD1	ENST00000639862.2	c.587C>T	p.Ser196Leu	missense_variant	2/10	5	NM_001170700.3	P2
DTHD1	ENST00000507598.5	c.332C>T	p.Ser111Leu	missense_variant	1/9	1		A2
DTHD1	ENST00000456874.3	c.212C>T	p.Ser71Leu	missense_variant	1/9	1		A2
DTHD1	ENST00000357504.7	c.17+2262C>T		intron_variant		2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Feb 05, 2024

The c.212C>T (p.S71L) alteration is located in exon 1 (coding exon 1) of the DTHD1 gene. This alteration results from a C to T substitution at nucleotide position 212, causing the serine (S) at amino acid position 71 to be replaced by a leucine (L). 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	Benign	0.069
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	8.1
Dann	Uncertain	0.98
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
Vest4		0.084, 0.087
MutPred		0.18		.;.;Gain of sheet (P = 0.0477);
MVP		0.048
ClinPred		0.13	T
GERP RS		2.7
Varity_R		0.055
gMVP		0.64

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: rs1032443046; hg19: chr4-36285913;