rs886037840

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-36282014-T-C
• chr4-36282014-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136536.5. 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.256T>C	p.Cys86Arg	missense	Exon 1 of 10	NP_001164171.2	A0A1W2PR94
	DTHD1	NM_001136536.5		c.2T>C	p.Met1?	start_lost	Exon 1 of 9	NP_001130008.2	Q6ZMT9-2
	DTHD1	NM_001378435.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 8	NP_001365364.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTHD1	ENST00000639862.2	TSL:5 MANE Select	c.256T>C	p.Cys86Arg	missense	Exon 1 of 10	ENSP00000492542.1	A0A1W2PR94
	DTHD1	ENST00000357504.7	TSL:2	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	ENSP00000350103.3	Q6ZMT9-2
	DTHD1	ENST00000903021.1		c.256T>C	p.Cys86Arg	missense	Exon 1 of 11	ENSP00000573080.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000695 AC: 1 AN: 143862 AF XY: 0.0000131

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

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

American (AMR) AF: 0.0000300 AC: 1 AN: 33302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24122

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

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75168

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

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5552

European-Non Finnish (NFE) AF: 0.0000150 AC: 16 AN: 1064832

Other (OTH) AF: 0.0000706 AC: 4 AN: 56642

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Muscular dystrophy;C0339527:Leber congenital amaurosis (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
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
PhyloP100		-0.086
ClinPred		0.098	T
GERP RS		-3.0
PromoterAI		0.065	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;