chr16-67943946-A-ACCGAGGATGACGGG

Variant names:

• chr16-67943946-A-ACCGAGGATGACGGG
• rs1485419925
• NM_005072.5:c.*880_*893dupCCCGTCATCCTCGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000229.2(LCAT):​c.142_154+1dupCCCGTCATCCTCGG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000718 in 1,393,084 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LCAT NM_000229.2 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.82
• Publications: 0 publications found

Genes affected

SLC12A4 (HGNC:10913): (solute carrier family 12 member 4) This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PP5: Variant 16-67943946-A-ACCGAGGATGACGGG is Pathogenic according to our data. Variant chr16-67943946-A-ACCGAGGATGACGGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3581217.Status of the report is criteria_provided_single_submitter, 1 stars.

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
	SLC12A4	NM_005072.5	MANE Select	c.*880_*893dupCCCGTCATCCTCGG		3_prime_UTR	Exon 24 of 24	NP_005063.1	Q9UP95-1
	LCAT	NM_000229.2	MANE Select	c.142_154+1dupCCCGTCATCCTCGG		splice_donor intron	N/A	NP_000220.1	P04180
	SLC12A4	NM_001145962.1		c.*880_*893dupCCCGTCATCCTCGG		3_prime_UTR	Exon 23 of 23	NP_001139434.1	Q9UP95-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A4	ENST00000316341.8	TSL:1 MANE Select	c.*880_*893dupCCCGTCATCCTCGG		3_prime_UTR	Exon 24 of 24	ENSP00000318557.3	Q9UP95-1
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.142_154+1dupCCCGTCATCCTCGG		splice_donor intron	N/A	ENSP00000264005.5	P04180
	LCAT	ENST00000575467.5	TSL:5	n.142_154+1dupCCCGTCATCCTCGG		splice_donor intron	N/A	ENSP00000460653.1	I3L3R0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000657 AC: 1 AN: 152108 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000886

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 686692

African (AFR) AF: 0.00 AC: 0 AN: 31524

American (AMR) AF: 0.00 AC: 0 AN: 35410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24878

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35644

South Asian (SAS) AF: 0.00 AC: 0 AN: 78612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4860

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075792

Other (OTH) AF: 0.00 AC: 0 AN: 57694

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Norum disease;C0342895:Fish-eye disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=3/97	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1485419925; hg19: chr16-67977849;