X-70239898-G-A

Variant names:

• chrX-70239898-G-A
• rs139503903
• NM_001013579.3:c.796G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001013579.3(AWAT1):​c.796G>A​(p.Gly266Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,208,461 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 193 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00048 (0 hom. 186 hem.)
• Consequence: AWAT1 NM_001013579.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.65

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant X-70239898-G-A is Benign according to our data. Variant chrX-70239898-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2349592.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AWAT1	NM_001013579.3	c.796G>A	p.Gly266Arg	missense_variant	Exon 6 of 7	ENST00000374521.4	NP_001013597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AWAT1	ENST00000374521.4	c.796G>A	p.Gly266Arg	missense_variant	Exon 6 of 7	1	NM_001013579.3	ENSP00000363645.3

Frequencies

GnomAD3 genomes AF: 0.000306 AC: 34 AN: 111018 Hom.: 0 Cov.: 22 AF XY: 0.000211 AC XY: 7 AN XY: 33228

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000961

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000672

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000509

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000383 AC: 70 AN: 182939 Hom.: 0 AF XY: 0.000444 AC XY: 30 AN XY: 67497

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000735

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000484 AC: 531 AN: 1097390 Hom.: 0 Cov.: 31 AF XY: 0.000513 AC XY: 186 AN XY: 362806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.000346

Gnomad4 NFE exome AF: 0.000571

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.000306 AC: 34 AN: 111071 Hom.: 0 Cov.: 22 AF XY: 0.000210 AC XY: 7 AN XY: 33291

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.0000959

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000672

Gnomad4 NFE AF: 0.000509

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000674 Hom.: 27

Bravo AF: 0.000310

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000491

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.796G>A (p.G266R) alteration is located in exon 6 (coding exon 6) of the AWAT1 gene. This alteration results from a G to A substitution at nucleotide position 796, causing the glycine (G) at amino acid position 266 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AWAT1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.95		Loss of catalytic residue at L267 (P = 0.1044);
MVP		0.73
MPC		0.75
ClinPred		0.48	T
GERP RS		5.4
Varity_R		0.81
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139503903; hg19: chrX-69459748;