Genetic Variant LORICRIN:p.Pro12Ser (chr1-153260983-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000427.3(LORICRIN):c.34C>T(p.Pro12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LORICRIN
NM_000427.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.977

Publications

0 publications found

Variant links:

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)

LORICRIN links:

ENSG00000301414 (HGNC:):

ENSG00000301414 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26275015).

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.34C>T	p.Pro12Ser	missense	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.34C>T	p.Pro12Ser	missense	Exon 2 of 2	ENSP00000357731.3	P23490
	ENSG00000301414	ENST00000778757.1		n.203+108C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442586

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717486

African (AFR)

AF:

0.00

AC:

AN:

31644

American (AMR)

AF:

0.00

AC:

AN:

42704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25678

East Asian (EAS)

AF:

0.00

AC:

AN:

37768

South Asian (SAS)

AF:

0.00

AC:

AN:

84086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103020

Other (OTH)

AF:

0.00

AC:

AN:

59632

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Loricrin keratoderma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.27

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.11

M_CAP

Benign

0.0074

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.98

PROVEAN

Pathogenic

-8.0

REVEL

Benign

0.14

Sift4G

Uncertain

0.051

Polyphen

1.0

Vest4

0.32

MutPred

0.16

Loss of catalytic residue at P12 (P = 0.0044)

MVP

0.51

ClinPred

0.40

GERP RS

3.2

Varity_R

0.66

gMVP

0.50

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over