4-36284195-C-G

Position:

• chr4-36284195-C-G

Variant summary

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

The NM_001170700.3(DTHD1):​c.491C>G​(p.Thr164Arg) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTHD1 NM_001170700.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.184

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]

DTHD1 (HGNC:):

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=0.07477999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTHD1	NM_001170700.3	c.491C>G	p.Thr164Arg	missense_variant	2/10	ENST00000639862.2	NP_001164171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTHD1	ENST00000639862.2	c.491C>G	p.Thr164Arg	missense_variant	2/10	5	NM_001170700.3	ENSP00000492542.1
DTHD1	ENST00000507598.5	c.236C>G	p.Thr79Arg	missense_variant	1/9	1		ENSP00000424426.1
DTHD1	ENST00000456874.3	c.116C>G	p.Thr39Arg	missense_variant	1/9	1		ENSP00000401597.2
DTHD1	ENST00000357504.7	c.17+2166C>G		intron_variant		2		ENSP00000350103.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jul 10, 2024

The c.116C>G (p.T39R) alteration is located in exon 1 (coding exon 1) of the DTHD1 gene. This alteration results from a C to G substitution at nucleotide position 116, causing the threonine (T) at amino acid position 39 to be replaced by an arginine (R). 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	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.0043	.;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.64	.;N;N
REVEL	Benign	0.018
Sift	Benign	0.048	.;D;T
Sift4G	Pathogenic	0.0	.;D;D
Vest4		0.12, 0.15
MutPred		0.12		.;.;Loss of glycosylation at S37 (P = 0.0658);
MVP		0.030
ClinPred		0.099	T
GERP RS		1.9
Varity_R		0.068
gMVP		0.59

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: chr4-36285817;