chrX-70044462-G-A

Position:

• chrX-70044462-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002254.1(AWAT2):​c.86C>T​(p.Thr29Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AWAT2 NM_001002254.1 missense, splice_region
• Scores: Splicing: ADA: 0.00002943
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.34

Genes affected

AWAT2 (HGNC:23251): (acyl-CoA wax alcohol acyltransferase 2) This gene encodes an enzyme belonging to the diacylglycerol acyltransferase family. This enzyme produces wax esters by the esterification of long chain (or wax) alcohols with acyl-CoA-derived fatty acids. It functions in lipid metabolism in the skin, mostly in undifferentiated peripheral sebocytes. This enzyme may also have acyl-CoA:retinol acyltransferase activities, where it catalyzes the synthesis of diacylglycerols and retinyl esters. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04711783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AWAT2	NM_001002254.1	c.86C>T	p.Thr29Ile	missense_variant, splice_region_variant	2/8	ENST00000276101.7	NP_001002254.1
AWAT2	XM_011530876.3	c.86C>T	p.Thr29Ile	missense_variant, splice_region_variant	2/8		XP_011529178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AWAT2	ENST00000276101.7	c.86C>T	p.Thr29Ile	missense_variant, splice_region_variant	2/8	5	NM_001002254.1	ENSP00000421172.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Mar 02, 2023

The c.86C>T (p.T29I) alteration is located in exon 2 (coding exon 2) of the AWAT2 gene. This alteration results from a C to T substitution at nucleotide position 86, causing the threonine (T) at amino acid position 29 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0010
DANN	Benign	0.33
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.016
Sift	Benign	0.40	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.47		Loss of catalytic residue at T29 (P = 0.0381);
MVP		0.043
MPC		0.36
ClinPred		0.071	T
GERP RS		-10
Varity_R		0.030
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.16
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: rs2020350146; hg19: chrX-69264312;