rs759773695

Variant names:

• chr2-20790332-C-G
• rs759773695
• NM_021925.4:c.221G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-20790332-C-G
• chr2-20790332-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021925.4(LDAH):​c.221G>C​(p.Arg74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R74H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDAH NM_021925.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• 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 2 ACMG points.

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

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.221G>C	p.Arg74Pro	missense	Exon 3 of 7	NP_068744.1	Q9H6V9-1
	LDAH	NM_001282723.2		c.221G>C	p.Arg74Pro	missense	Exon 3 of 6	NP_001269652.1	B4DRG3
	LDAH	NM_001282721.2		c.-170G>C		5_prime_UTR	Exon 2 of 6	NP_001269650.1	Q9H6V9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDAH	ENST00000237822.8	TSL:1 MANE Select	c.221G>C	p.Arg74Pro	missense	Exon 3 of 7	ENSP00000237822.3	Q9H6V9-1
	LDAH	ENST00000911673.1		c.221G>C	p.Arg74Pro	missense	Exon 3 of 8	ENSP00000581732.1
	LDAH	ENST00000381090.7	TSL:5	c.221G>C	p.Arg74Pro	missense	Exon 3 of 9	ENSP00000370480.3	B5MDU6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111898

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Benign	0.043
Eigen_PC	Benign	-0.00095
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.64	T
PhyloP100		-0.014
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Benign	0.030	D
Sift4G	Uncertain	0.059	T
Polyphen		0.99	D
Vest4		0.60
MutPred		0.54		Loss of catalytic residue at R74 (P = 0.0256)
MVP		0.47
MPC		0.56
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.74
gMVP		0.54
Mutation Taster		=49/51	disease causing

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: rs759773695; hg19: chr2-20990092;