Genetic Variant LORICRIN:p.Gly85Arg (chr1-153261202-G-C) – 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>C(p.Gly85Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,344,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Synonymous variant affecting the same amino acid position (i.e. G85G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000061 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

LORICRIN
NM_000427.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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=0.14014828).

BS2

High AC in GnomAd4 at 9 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>C	p.Gly85Arg	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>C	p.Gly85Arg	missense	Exon 2 of 2	ENSP00000357731.3	P23490
	ENSG00000301414	ENST00000778757.1		n.203+327G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000608

AC:

AN:

148012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00184

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

GnomAD2 exomes

AF:

0.000236

AC:

AN:

4238

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00943

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1196792

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

582048

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:

0.000513

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:

0.00000609

AC:

AN:

985552

Other (OTH)

AF:

0.0000610

AC:

AN:

49198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

AF:

0.0000608

AC:

AN:

148142

Hom.:

Cov.:

AF XY:

0.0000829

AC XY:

AN XY:

72346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40138

American (AMR)

AF:

0.00

AC:

AN:

14930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00184

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:

66734

Other (OTH)

AF:

0.00

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.27

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.067

M_CAP

Benign

0.057

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.29

PROVEAN

Pathogenic

-6.8

REVEL

Benign

0.087

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.19

MutPred

0.31

Gain of methylation at G85 (P = 0.0049)

MVP

0.64

ClinPred

0.37

GERP RS

2.1

Varity_R

0.40

gMVP

0.22

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over