2-20801370-T-C

Position:

• chr2-20801370-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021925.4(LDAH):​c.94A>G​(p.Thr32Ala) variant causes a missense 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDAH NM_021925.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

LDAH (HGNC:26145): (lipid droplet associated hydrolase) Predicted to enable lipase activity. Predicted to be involved in lipid storage. Predicted to be located in endoplasmic reticulum. Predicted to be active in lipid droplet. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19262084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDAH	NM_021925.4	c.94A>G	p.Thr32Ala	missense_variant	2/7	ENST00000237822.8	NP_068744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDAH	ENST00000237822.8	c.94A>G	p.Thr32Ala	missense_variant	2/7	1	NM_021925.4	ENSP00000237822	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jul 27, 2022

The c.94A>G (p.T32A) alteration is located in exon 2 (coding exon 1) of the LDAH gene. This alteration results from a A to G substitution at nucleotide position 94, causing the threonine (T) at amino acid position 32 to be replaced by an alanine (A). 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	0.096
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;T;T;T;.;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PROVEAN	Benign	-1.6	N;N;N;N;.;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.13	T;T;T;T;.;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;.;T;D
Polyphen		0.73	P;.;P;P;.;.;.;.
Vest4		0.27
MutPred		0.42		Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);Gain of catalytic residue at T32 (P = 0.0252);
MVP		0.43
MPC		0.12
ClinPred		0.35	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-21001130;