chr1-153261102-C-A

Variant names:

• chr1-153261102-C-A
• rs1143389
• NM_000427.3:c.153C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000427.3(LORICRIN):​c.153C>A​(p.Cys51*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000785 in 1,273,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C51C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: LORICRIN NM_000427.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• Publications: 0 publications found

Genes affected

LORICRIN (HGNC:6663): (loricrin cornified envelope precursor protein) This gene encodes loricrin, a major protein component of the cornified cell envelope found in terminally differentiated epidermal cells. Mutations in this gene are associated with Vohwinkel's syndrome and progressive symmetric erythrokeratoderma, both inherited skin diseases. [provided by RefSeq, Jul 2008]

LORICRIN Gene-Disease associations (from GenCC):

• loricrin keratoderma

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000301414 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000427.3. 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
	LORICRIN	NM_000427.3	MANE Select	c.153C>A	p.Cys51*	stop_gained	Exon 2 of 2	NP_000418.2	P23490

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LORICRIN	ENST00000368742.4	TSL:1 MANE Select	c.153C>A	p.Cys51*	stop_gained	Exon 2 of 2	ENSP00000357731.3	P23490
	ENSG00000301414	ENST00000778757.1		n.203+227C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 7.85e-7 AC: 1 AN: 1273904 Hom.: 0 Cov.: 48 AF XY: 0.00000160 AC XY: 1 AN XY: 624920

African (AFR) AF: 0.0000390 AC: 1 AN: 25628

American (AMR) AF: 0.00 AC: 0 AN: 19770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20266

East Asian (EAS) AF: 0.00 AC: 0 AN: 29162

South Asian (SAS) AF: 0.00 AC: 0 AN: 63698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1024258

Other (OTH) AF: 0.00 AC: 0 AN: 52566

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Benign	-0.55
CADD	Pathogenic	28
DANN	Benign	0.91
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.20	N
PhyloP100		-0.97
Vest4		0.55
GERP RS		-7.2
Mutation Taster		=179/21	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: rs1143389; hg19: chr1-153233578;