Genetic Variant LCE1D:p.Thr21Pro (chr1-152797855-A-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_178352.3(LCE1D):c.61A>C(p.Thr21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,433,062 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000055 ( 1 hom., cov: 21)

Exomes 𝑓: 0.000056 ( 12 hom. )

Consequence

LCE1D
NM_178352.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.948

Variant links:

Genes affected

LCE1D (HGNC:29465): (late cornified envelope 1D) Enables identical protein binding activity. Involved in cognition. Acts upstream of or within cellular response to calcium ion. Located in cornified envelope and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LCE1D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013079613).

BP6

Variant 1-152797855-A-C is Benign according to our data. Variant chr1-152797855-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2345802.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCE1D	NM_178352.3 link	c.61A>C	p.Thr21Pro	missense_variant	Exon 2 of 2	ENST00000326233.7	NP_848129.1	Q5T752

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCE1D	ENST00000326233.7 link	c.61A>C	p.Thr21Pro	missense_variant	Exon 2 of 2	5	NM_178352.3	ENSP00000316737.6		Q5T752

Frequencies

GnomAD3 genomes

AF:

0.0000547

AC:

AN:

128048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000572

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:

0.0000885

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

230226

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

124660

show subpopulations

Gnomad AFR exome

AF:

0.000404

Gnomad AMR exome

AF:

0.000210

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000678

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000559

AC:

AN:

1305014

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

650068

show subpopulations

Gnomad4 AFR exome

AF:

0.000408

Gnomad4 AMR exome

AF:

0.000186

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000108

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000400

Gnomad4 OTH exome

AF:

0.0000547

GnomAD4 genome

AF:

0.0000547

AC:

AN:

128048

Hom.:

Cov.:

AF XY:

0.0000801

AC XY:

AN XY:

62456

show subpopulations

Gnomad4 AFR

AF:

0.0000572

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000885

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000114

AC:

Asia WGS

AF:

0.000294

AC:

AN:

3414

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 16, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.46

DANN

Benign

0.89

DEOGEN2

Benign

0.022

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.13

M_CAP

Benign

0.011

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-1.8

PROVEAN

Benign

1.7

REVEL

Benign

0.083

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.081

MVP

0.099

MPC

0.38

ClinPred

0.0076

GERP RS

3.0

Varity_R

0.14

gMVP

0.0099

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over