rs886037840

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001170700.3(DTHD1):c.256T>C(p.Cys86Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,373,018 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.000017 ( 0 hom. )

Consequence

DTHD1
NM_001170700.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.0860

Publications

0 publications found

Variant links:

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

DTHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.05490741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTHD1	NM_001170700.3 link	c.256T>C	p.Cys86Arg	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 link	c.256T>C	p.Cys86Arg	missense_variant	Exon 1 of 10	5	NM_001170700.3	ENSP00000492542.1
DTHD1	ENST00000357504.7 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	2		ENSP00000350103.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000695

AC:

AN:

143862

AF XY:

0.0000131

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000459

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:

0.0000168

AC:

AN:

1373018

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

677118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30646

American (AMR)

AF:

0.0000300

AC:

AN:

33302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24122

East Asian (EAS)

AF:

0.00

AC:

AN:

34968

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47786

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5552

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

1064832

Other (OTH)

AF:

0.0000706

AC:

AN:

56642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Muscular dystrophy;C0339527:Leber congenital amaurosis

Uncertain:1

Feb 01, 2013

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the DTHD1 mRNA. The next in-frame methionine is located at codon 41. This variant is present in population databases (no rsID available, gnomAD 0.005%). Disruption of the initiator codon has been observed in individual(s) with Leber congenital amaurosis (PMID: 23105016). ClinVar contains an entry for this variant (Variation ID: 242990). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.43

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.34

M_CAP

Benign

0.010

MetaRNN

Benign

0.055

PhyloP100

-0.086

ClinPred

0.098

GERP RS

-3.0

PromoterAI

0.065

Neutral

(source)

Mutation Taster

=49/151

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over