19-10287763-G-C

Position:

chr19-10287763-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001544.5(ICAM4):c.622G>C(p.Val208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,746 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 3 hom. )

Consequence

ICAM4
NM_001544.5 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.477

Variant links:

Genes affected

ICAM4 (HGNC:5347): (intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)) This gene encodes the Landsteiner-Wiener (LW) blood group antigen(s) that belongs to the immunoglobulin (Ig) superfamily, and that shares similarity with the intercellular adhesion molecule (ICAM) protein family. This ICAM protein contains 2 Ig-like C2-type domains and binds to the leukocyte adhesion LFA-1 protein. The molecular basis of the LW(A)/LW(B) blood group antigens is a single aa variation at position 100; Gln-100=LW(A) and Arg-100=LW(B). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ICAM4 links:

ICAM4-AS1 (HGNC:55990): (ICAM4 antisense RNA 1)

ICAM4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033723414).

BP6

Variant 19-10287763-G-C is Benign according to our data. Variant chr19-10287763-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3037227.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00461 (701/152224) while in subpopulation AFR AF= 0.0161 (667/41536). AF 95% confidence interval is 0.015. There are 4 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICAM4	NM_001544.5 linkuse as main transcript	c.622G>C	p.Val208Leu	missense_variant	2/3	ENST00000380770.5
ICAM4	NM_001039132.3 linkuse as main transcript	c.545G>C	p.Arg182Pro	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICAM4	ENST00000380770.5 linkuse as main transcript	c.622G>C	p.Val208Leu	missense_variant	2/3	1	NM_001544.5	P2	Q14773-1
ICAM4	ENST00000340992.4 linkuse as main transcript	c.545G>C	p.Arg182Pro	missense_variant	2/3	1			Q14773-3
ICAM4-AS1	ENST00000589379.1 linkuse as main transcript	n.1257C>G		non_coding_transcript_exon_variant	1/1
ICAM4	ENST00000393717.2 linkuse as main transcript	c.622G>C	p.Val208Leu	missense_variant	2/2	2		A2	Q14773-2

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

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:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00109

AC:

273

AN:

251126

Hom.:

AF XY:

0.000862

AC XY:

117

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0152

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000465

AC:

680

AN:

1461522

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

277

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0171

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.00461

AC:

701

AN:

152224

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0161

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.00539

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00144

AC:

175

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ICAM4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.1

DANN

Benign

0.74

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

REVEL

Benign

0.034

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.15

MVP

0.13

MPC

1.3

ClinPred

0.072

GERP RS

-7.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.56

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