4-36284205-G-C

Variant names:

• chr4-36284205-G-C
• rs564475767
• NM_001170700.3:c.501G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001170700.3(DTHD1):​c.501G>C​(p.Glu167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E167E) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DTHD1 NM_001170700.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.961
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• LCAT deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05954504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170700.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTHD1	NM_001170700.3	MANE Select	c.501G>C	p.Glu167Asp	missense	Exon 2 of 10	NP_001164171.2	A0A1W2PR94
	DTHD1	NM_001136536.5		c.17+2176G>C		intron	N/A	NP_001130008.2	Q6ZMT9-2
	DTHD1	NM_001378435.1		c.17+2176G>C		intron	N/A	NP_001365364.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTHD1	ENST00000639862.2	TSL:5 MANE Select	c.501G>C	p.Glu167Asp	missense	Exon 2 of 10	ENSP00000492542.1	A0A1W2PR94
	DTHD1	ENST00000507598.5	TSL:1	c.246G>C	p.Glu82Asp	missense	Exon 1 of 9	ENSP00000424426.1	D6RB49
	DTHD1	ENST00000456874.3	TSL:1	c.126G>C	p.Glu42Asp	missense	Exon 1 of 9	ENSP00000401597.2	Q6ZMT9-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.96
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.041
Sift	Benign	0.55	T
Sift4G	Benign	0.61	T
Vest4		0.073
MutPred		0.11		Gain of glycosylation at Y46 (P = 0.0017)
MVP		0.014
ClinPred		0.073	T
GERP RS		2.9
PromoterAI		-0.015	Neutral
Varity_R		0.054
gMVP		0.25
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs564475767; hg19: chr4-36285827;