chr4-36282014-T-G

Variant names:

• chr4-36282014-T-G
• rs886037840
• NM_001170700.3:c.256T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170700.3(DTHD1):​c.256T>G​(p.Cys86Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,373,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C86Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DTHD1 NM_001170700.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07585958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTHD1	NM_001170700.3	c.256T>G	p.Cys86Gly	missense_variant	Exon 1 of 10	ENST00000639862.2	NP_001164171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTHD1	ENST00000639862.2	c.256T>G	p.Cys86Gly	missense_variant	Exon 1 of 10	5	NM_001170700.3	ENSP00000492542.1
DTHD1	ENST00000357504.7	c.2T>G	p.Met1?	start_lost	Exon 1 of 9	2		ENSP00000350103.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1373016 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 677118

African (AFR) AF: 0.00 AC: 0 AN: 30646

American (AMR) AF: 0.00 AC: 0 AN: 33302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24120

East Asian (EAS) AF: 0.00 AC: 0 AN: 34968

South Asian (SAS) AF: 0.00 AC: 0 AN: 75168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1064832

Other (OTH) AF: 0.00 AC: 0 AN: 56642

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.80
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.076	T
PhyloP100		-0.086
ClinPred		0.49	T
GERP RS		-3.0
PromoterAI		0.035	Neutral
Mutation Taster		=49/151	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037840; hg19: chr4-36283636;