X-70234703-A-G

Variant names:

• chrX-70234703-A-G
• rs747940140
• NM_001013579.3:c.8A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001013579.3(AWAT1):​c.8A>G​(p.His3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,097,043 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000013 (0 hom. 5 hem.)
• Consequence: AWAT1 NM_001013579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0450

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048294783).
• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AWAT1	NM_001013579.3	c.8A>G	p.His3Arg	missense_variant	Exon 1 of 7	ENST00000374521.4	NP_001013597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AWAT1	ENST00000374521.4	c.8A>G	p.His3Arg	missense_variant	Exon 1 of 7	1	NM_001013579.3	ENSP00000363645.3
AWAT1	ENST00000480702.1	n.49A>G		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000218 AC: 4 AN: 183079 Hom.: 0 AF XY: 0.0000444 AC XY: 3 AN XY: 67597

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097043 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 5 AN XY: 362485

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: 0.0000143

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8A>G (p.H3R) alteration is located in exon 1 (coding exon 1) of the AWAT1 gene. This alteration results from a A to G substitution at nucleotide position 8, causing the histidine (H) at amino acid position 3 to be replaced by an arginine (R). 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	Benign	0.051
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.6
DANN	Benign	0.14
DEOGEN2	Benign	0.040	T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.027
Sift	Benign	0.91	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.11		Loss of ubiquitination at K5 (P = 0.0236);
MVP		0.33
MPC		0.20
ClinPred		0.013	T
GERP RS		-4.6
Varity_R		0.034
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs747940140; hg19: chrX-69454553;