Genetic Variant LORICRIN:p.Gly85Ser (chr1-153261202-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_000427.3(LORICRIN):c.253G>A(p.Gly85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000585 in 1,196,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G85R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LORICRIN
NM_000427.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.295

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21305329).

BS2

High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.253G>A	p.Gly85Ser	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.253G>A	p.Gly85Ser	missense	Exon 2 of 2	ENSP00000357731.3	P23490
	ENSG00000301414	ENST00000778757.1		n.203+327G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148006

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000585

AC:

AN:

1196790

Hom.:

Cov.:

AF XY:

0.00000687

AC XY:

AN XY:

582046

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22936

American (AMR)

AF:

0.00

AC:

AN:

10096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16232

East Asian (EAS)

AF:

0.00

AC:

AN:

27296

South Asian (SAS)

AF:

0.00

AC:

AN:

52422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3592

European-Non Finnish (NFE)

AF:

0.00000710

AC:

AN:

985550

Other (OTH)

AF:

0.00

AC:

AN:

49198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

148136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72346

African (AFR)

AF:

0.00

AC:

AN:

40136

American (AMR)

AF:

0.00

AC:

AN:

14928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

4892

South Asian (SAS)

AF:

0.00

AC:

AN:

4556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66732

Other (OTH)

AF:

0.00

AC:

AN:

2024

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.22

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.038

M_CAP

Benign

0.034

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.29

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.057

Sift4G

Benign

0.068

Polyphen

0.99

Vest4

0.23

MutPred

0.31

Gain of glycosylation at G85 (P = 0.0022)

MVP

0.55

ClinPred

0.28

GERP RS

2.1

Varity_R

0.58

gMVP

0.18

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over