chr4-36284302-C-A

Variant names:

• chr4-36284302-C-A
• rs747817328
• NM_001170700.3:c.598C>A

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.598C>A​(p.Arg200Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000325 in 1,536,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: DTHD1 NM_001170700.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.186
• 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=0.0407463).

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.598C>A	p.Arg200Ser	missense	Exon 2 of 10	NP_001164171.2	A0A1W2PR94
	DTHD1	NM_001136536.5		c.17+2273C>A		intron	N/A	NP_001130008.2	Q6ZMT9-2
	DTHD1	NM_001378435.1		c.17+2273C>A		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.598C>A	p.Arg200Ser	missense	Exon 2 of 10	ENSP00000492542.1	A0A1W2PR94
	DTHD1	ENST00000507598.5	TSL:1	c.343C>A	p.Arg115Ser	missense	Exon 1 of 9	ENSP00000424426.1	D6RB49
	DTHD1	ENST00000456874.3	TSL:1	c.223C>A	p.Arg75Ser	missense	Exon 1 of 9	ENSP00000401597.2	Q6ZMT9-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000718 AC: 1 AN: 139282 AF XY: 0.0000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1384870 Hom.: 0 Cov.: 30 AF XY: 0.00000439 AC XY: 3 AN XY: 683354

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.0000280 AC: 1 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078844

Other (OTH) AF: 0.00 AC: 0 AN: 57912

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000181790), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000481 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.028
DANN	Benign	0.46
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.19
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.017
Sift	Benign	0.36	T
Sift4G	Benign	0.60	T
Vest4		0.018
MutPred		0.24		Loss of sheet (P = 0.0817)
MVP		0.014
ClinPred		0.070	T
GERP RS		-3.8
PromoterAI		-0.015	Neutral
Varity_R		0.075
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs747817328; hg19: chr4-36285924;