X-70237205-G-T

Position:

• chrX-70237205-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001013579.3(AWAT1):​c.417G>T​(p.Trp139Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: AWAT1 NM_001013579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.100

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AWAT1	NM_001013579.3	c.417G>T	p.Trp139Cys	missense_variant	4/7	ENST00000374521.4	NP_001013597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AWAT1	ENST00000374521.4	c.417G>T	p.Trp139Cys	missense_variant	4/7	1	NM_001013579.3	ENSP00000363645	P1
AWAT1	ENST00000480702.1	n.458G>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096208 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 361686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.417G>T (p.W139C) alteration is located in exon 4 (coding exon 4) of the AWAT1 gene. This alteration results from a G to T substitution at nucleotide position 417, causing the tryptophan (W) at amino acid position 139 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0061	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0905);
MVP		0.73
MPC		0.84
ClinPred		0.88	D
GERP RS		4.5
Varity_R		0.31
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69457055;