16-67943479-T-C

Variant names:

• chr16-67943479-T-C
• rs1109166
• NM_005072.5:c.*1361A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005072.5(SLC12A4):​c.*1361A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 528,266 control chromosomes in the GnomAD database, including 20,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (11003 hom., cov: 33)
  • Exomes 𝑓: 0.20 (9262 hom.)
• Consequence: SLC12A4 NM_005072.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.132
• Publications: 47 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• LCAT deficiency

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-67943479-T-C is Benign according to our data. Variant chr16-67943479-T-C is described in ClinVar as Benign. ClinVar VariationId is 1221653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A4	NM_005072.5	c.*1361A>G		3_prime_UTR_variant	Exon 24 of 24	ENST00000316341.8	NP_005063.1
LCAT	NM_000229.2	c.155-267A>G		intron_variant	Intron 1 of 5	ENST00000264005.10	NP_000220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A4	ENST00000316341.8	c.*1361A>G		3_prime_UTR_variant	Exon 24 of 24	1	NM_005072.5	ENSP00000318557.3
LCAT	ENST00000264005.10	c.155-267A>G		intron_variant	Intron 1 of 5	1	NM_000229.2	ENSP00000264005.5
LCAT	ENST00000570980.1	c.-329A>G		5_prime_UTR_variant	Exon 1 of 5	2		ENSP00000464651.1
LCAT	ENST00000575467.5	n.155-290A>G		intron_variant	Intron 1 of 5	5		ENSP00000460653.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47984 AN: 151972 Hom.: 10968 Cov.: 33

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.287

GnomAD4 exome AF: 0.200 AC: 75377 AN: 376176 Hom.: 9262 Cov.: 0 AF XY: 0.201 AC XY: 39969 AN XY: 199076

African (AFR) AF: 0.645 AC: 7072 AN: 10962

American (AMR) AF: 0.220 AC: 3663 AN: 16672

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 2254 AN: 11646

East Asian (EAS) AF: 0.132 AC: 3106 AN: 23512

South Asian (SAS) AF: 0.249 AC: 11267 AN: 45328

European-Finnish (FIN) AF: 0.194 AC: 4255 AN: 21912

Middle Eastern (MID) AF: 0.247 AC: 401 AN: 1622

European-Non Finnish (NFE) AF: 0.174 AC: 38682 AN: 222754

Other (OTH) AF: 0.215 AC: 4677 AN: 21768

GnomAD4 genome AF: 0.316 AC: 48074 AN: 152090 Hom.: 11003 Cov.: 33 AF XY: 0.314 AC XY: 23334 AN XY: 74360

African (AFR) AF: 0.652 AC: 27043 AN: 41468

American (AMR) AF: 0.239 AC: 3660 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 678 AN: 3468

East Asian (EAS) AF: 0.115 AC: 594 AN: 5170

South Asian (SAS) AF: 0.244 AC: 1176 AN: 4824

European-Finnish (FIN) AF: 0.203 AC: 2153 AN: 10588

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11929 AN: 67974

Other (OTH) AF: 0.290 AC: 611 AN: 2108

Alfa AF: 0.243 Hom.: 8015

Bravo AF: 0.329

Asia WGS AF: 0.255 AC: 890 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31039173, 25814643)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.66
PhyloP100		0.13
PromoterAI		0.0098	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1109166; hg19: chr16-67977382;