rs202017590

Variant names:

• chr16-67940188-G-A
• rs202017590
• NM_000229.2:c.1039C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-67940188-G-A
• chr16-67940188-G-C

Variant summary

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

The NM_000229.2(LCAT):​c.1039C>T​(p.Arg347Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,612,406 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.169
• Publications: 5 publications found

Genes affected

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

LCAT Gene-Disease associations (from GenCC):

• fish eye disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• LCAT deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Norum disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000229.2. 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
	LCAT	NM_000229.2	MANE Select	c.1039C>T	p.Arg347Cys	missense	Exon 6 of 6	NP_000220.1	P04180

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.1039C>T	p.Arg347Cys	missense	Exon 6 of 6	ENSP00000264005.5	P04180
	LCAT	ENST00000570369.5	TSL:2	c.155-114C>T		intron	N/A	ENSP00000459014.1	I3L1Q6
	LCAT	ENST00000573538.5	TSL:3	n.*360C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000463220.1	J3QKT0

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 151522 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000153 AC: 38 AN: 249164 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000798

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1460766 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 726726

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52342

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

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1111984

Other (OTH) AF: 0.000116 AC: 7 AN: 60374

GnomAD4 genome AF: 0.000138 AC: 21 AN: 151640 Hom.: 1 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74128

African (AFR) AF: 0.0000484 AC: 2 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5104

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67782

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Norum disease;C0342895:Fish-eye disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.17
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.073	T
Polyphen		0.39	B
Vest4		0.73
MVP		0.63
MPC		0.58
ClinPred		0.11	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.84
Mutation Taster		=37/63	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: rs202017590; hg19: chr16-67974091;