rs12507599

Variant names:

• chr4-36308427-C-T
• rs12507599
• NM_001170700.3:c.2029C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001170700.3(DTHD1):​c.2029C>T​(p.Arg677Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,551,206 control chromosomes in the GnomAD database, including 52,327 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R677H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5281 hom., cov: 32)
  • Exomes 𝑓: 0.26 (47046 hom.)
• Consequence: DTHD1 NM_001170700.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.521
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010963976).
• BP6: Variant 4-36308427-C-T is Benign according to our data. Variant chr4-36308427-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

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.2029C>T	p.Arg677Cys	missense	Exon 7 of 10	NP_001164171.2	A0A1W2PR94
	DTHD1	NM_001136536.5		c.1159C>T	p.Arg387Cys	missense	Exon 6 of 9	NP_001130008.2	Q6ZMT9-2
	DTHD1	NM_001378435.1		c.1096C>T	p.Arg366Cys	missense	Exon 6 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.2029C>T	p.Arg677Cys	missense	Exon 7 of 10	ENSP00000492542.1	A0A1W2PR94
	DTHD1	ENST00000507598.5	TSL:1	c.1774C>T	p.Arg592Cys	missense	Exon 6 of 9	ENSP00000424426.1	D6RB49
	DTHD1	ENST00000456874.3	TSL:1	c.1654C>T	p.Arg552Cys	missense	Exon 6 of 9	ENSP00000401597.2	Q6ZMT9-1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39550 AN: 151962 Hom.: 5285 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.257

GnomAD2 exomes AF: 0.287 AC: 45202 AN: 157372 AF XY: 0.291

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.256 AC: 358745 AN: 1399126 Hom.: 47046 Cov.: 34 AF XY: 0.260 AC XY: 179415 AN XY: 690060

African (AFR) AF: 0.259 AC: 8187 AN: 31592

American (AMR) AF: 0.341 AC: 12160 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6472 AN: 25176

East Asian (EAS) AF: 0.282 AC: 10080 AN: 35734

South Asian (SAS) AF: 0.380 AC: 30084 AN: 79216

European-Finnish (FIN) AF: 0.228 AC: 11267 AN: 49344

Middle Eastern (MID) AF: 0.257 AC: 1466 AN: 5702

European-Non Finnish (NFE) AF: 0.244 AC: 263281 AN: 1078632

Other (OTH) AF: 0.271 AC: 15748 AN: 58026

GnomAD4 genome AF: 0.260 AC: 39566 AN: 152080 Hom.: 5281 Cov.: 32 AF XY: 0.265 AC XY: 19704 AN XY: 74360

African (AFR) AF: 0.254 AC: 10518 AN: 41466

American (AMR) AF: 0.321 AC: 4915 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3468

East Asian (EAS) AF: 0.340 AC: 1754 AN: 5164

South Asian (SAS) AF: 0.377 AC: 1815 AN: 4818

European-Finnish (FIN) AF: 0.224 AC: 2369 AN: 10590

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16335 AN: 67972

Other (OTH) AF: 0.256 AC: 542 AN: 2114

Alfa AF: 0.248 Hom.: 9813

Bravo AF: 0.267

TwinsUK AF: 0.234 AC: 869

ALSPAC AF: 0.242 AC: 934

ESP6500AA AF: 0.246 AC: 340

ESP6500EA AF: 0.259 AC: 823

ExAC AF: 0.277 AC: 6868

Asia WGS AF: 0.346 AC: 1209 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.1
DANN	Benign	0.83
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.52
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.092
Sift	Benign	0.088	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.0040	B
Vest4		0.097
ClinPred		0.022	T
GERP RS		2.0
Varity_R		0.065
gMVP		0.28
Mutation Taster		=95/5	polymorphism (auto)

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: rs12507599; hg19: chr4-36310049; COSMIC: COSV62628243; COSMIC: COSV62628243;