Genetic Variant DTHD1:p.Thr164Lys (chr4-36284195-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001170700.3(DTHD1):c.491C>A(p.Thr164Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,537,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T164R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DTHD1
NM_001170700.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.184

Publications

1 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038336188).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DTHD1	NM_001170700.3	MANE Select	c.491C>A	p.Thr164Lys	missense	Exon 2 of 10	NP_001164171.2	A0A1W2PR94
DTHD1	NM_001136536.5		c.17+2166C>A		intron	N/A	NP_001130008.2	Q6ZMT9-2
DTHD1	NM_001378435.1		c.17+2166C>A		intron	N/A	NP_001365364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DTHD1	ENST00000639862.2	TSL:5 MANE Select	c.491C>A	p.Thr164Lys	missense	Exon 2 of 10	ENSP00000492542.1	A0A1W2PR94
DTHD1	ENST00000507598.5	TSL:1	c.236C>A	p.Thr79Lys	missense	Exon 1 of 9	ENSP00000424426.1	D6RB49
DTHD1	ENST00000456874.3	TSL:1	c.116C>A	p.Thr39Lys	missense	Exon 1 of 9	ENSP00000401597.2	Q6ZMT9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000649

AC:

AN:

138708

AF XY:

0.0000538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000754

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000108

AC:

AN:

1384886

Hom.:

Cov.:

AF XY:

0.00000878

AC XY:

AN XY:

683358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31594

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.000308

AC:

AN:

35720

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078856

Other (OTH)

AF:

0.0000173

AC:

AN:

57912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000577

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.3

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0038

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.48

M_CAP

Benign

0.0056

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

PhyloP100

-0.18

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.37

REVEL

Benign

0.0070

Sift

Benign

0.070

Sift4G

Pathogenic

0.0

Vest4

0.060

MutPred

0.20

Gain of ubiquitination at T39 (P = 0.0054)

MVP

0.030

ClinPred

0.033

GERP RS

1.9

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.060

gMVP

0.59

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over