2-20687045-T-A

Variant names:

• chr2-20687045-T-A
• rs771062746
• NM_021925.4:c.836A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021925.4(LDAH):​c.836A>T​(p.Tyr279Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y279C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDAH NM_021925.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34675694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021925.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDAH	NM_021925.4	MANE Select	c.836A>T	p.Tyr279Phe	missense	Exon 7 of 7	NP_068744.1	Q9H6V9-1
	LDAH	NM_001282719.2		c.710A>T	p.Tyr237Phe	missense	Exon 6 of 6	NP_001269648.1	A0A0A0MSH6
	LDAH	NM_001282720.2		c.692A>T	p.Tyr231Phe	missense	Exon 6 of 6	NP_001269649.1	Q9H6V9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDAH	ENST00000237822.8	TSL:1 MANE Select	c.836A>T	p.Tyr279Phe	missense	Exon 7 of 7	ENSP00000237822.3	Q9H6V9-1
	LDAH	ENST00000911673.1		c.989A>T	p.Tyr330Phe	missense	Exon 8 of 8	ENSP00000581732.1
	LDAH	ENST00000381090.7	TSL:5	c.836A>T	p.Tyr279Phe	missense	Exon 7 of 9	ENSP00000370480.3	B5MDU6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461758 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
Eigen	Benign	0.085
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.8
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Benign	0.076	T
Sift4G	Benign	0.13	T
Polyphen		0.36	B
Vest4		0.17
MutPred		0.78		Loss of ubiquitination at K283 (P = 0.063)
MVP		0.42
MPC		0.20
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.33
gMVP		0.65
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs771062746; hg19: chr2-20886805;