chr4-36282014-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001136536.5(DTHD1):​c.2T>C​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DTHD1 NM_001136536.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.0860

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 41 codons. Genomic position: 36290476. Lost 0.065 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000695 AC: 1 AN: 143862 Hom.: 0 AF XY: 0.0000131 AC XY: 1 AN XY: 76344

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 SAS 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: 23 AN: 1373018 Hom.: 0 Cov.: 31 AF XY: 0.0000236 AC XY: 16 AN XY: 677118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000150

Gnomad4 OTH exome AF: 0.0000706

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.43
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.055	T
ClinPred		0.098	T
GERP RS		-3.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037840; hg19: chr4-36283636;