Genetic Variant AWAT1:p.Ala50Val (chrX-70235788-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001013579.3(AWAT1):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,206,292 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000021 ( 0 hom. 7 hem. )

Consequence

AWAT1
NM_001013579.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.140

Publications

0 publications found

Variant links:

Genes affected

AWAT1 (HGNC:23252): (acyl-CoA wax alcohol acyltransferase 1) The protein encoded by this gene belongs to the diacylglycerol acyltransferase family. It esterifies long chain (wax) alcohols with acyl-CoA-derived fatty acids to produce wax esters. Wax esters are enriched in sebum, suggesting that this enzyme plays a central role in lipid metabolism in skin. Consistent with this observation, this protein is predominantly expressed in the sebaceous gland of the skin. [provided by RefSeq, Sep 2009]

AWAT1 links:

ENSG00000294004 (HGNC:):

ENSG00000294004 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15669423).

BP6

Variant X-70235788-C-T is Benign according to our data. Variant chrX-70235788-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2232116.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013579.3. 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
	AWAT1	NM_001013579.3	MANE Select	c.149C>T	p.Ala50Val	missense	Exon 2 of 7	NP_001013597.1	Q58HT5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AWAT1	ENST00000374521.4	TSL:1 MANE Select	c.149C>T	p.Ala50Val	missense	Exon 2 of 7	ENSP00000363645.3	Q58HT5
AWAT1	ENST00000480702.1	TSL:3	n.190C>T		non_coding_transcript_exon	Exon 2 of 4
ENSG00000294004	ENST00000720464.1		n.136+16634G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111064

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:

0.00

Gnomad SAS

AF:

0.000390

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000755

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183366

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000210

AC:

AN:

1095173

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

360613

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26344

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.00

AC:

AN:

30192

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000203

AC:

AN:

839359

Other (OTH)

AF:

0.0000652

AC:

AN:

46000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000450

AC:

AN:

111119

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33311

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30548

American (AMR)

AF:

0.00

AC:

AN:

10442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3528

South Asian (SAS)

AF:

0.000391

AC:

AN:

2558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000755

AC:

AN:

52973

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000108

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.084

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.11

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.048

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.41

M_CAP

Benign

0.0024

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.060

PhyloP100

-0.14

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.22

REVEL

Benign

0.011

Sift

Benign

1.0

Sift4G

Benign

0.99

Polyphen

0.0010

Vest4

0.18

MutPred

0.49

Loss of catalytic residue at A50 (P = 0.077)

MVP

0.64

MPC

0.16

ClinPred

0.013

GERP RS

-2.1

Varity_R

0.037

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over