chr19-10287563-C-T

Position:

• chr19-10287563-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001544.5(ICAM4):​c.422C>T​(p.Pro141Leu) 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. 13/18 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)
• Consequence: ICAM4 NM_001544.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4199043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICAM4	NM_001544.5	c.422C>T	p.Pro141Leu	missense_variant	2/3	ENST00000380770.5	NP_001535.1
ICAM4	NM_001039132.3	c.395-50C>T		intron_variant			NP_001034221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICAM4	ENST00000380770.5	c.422C>T	p.Pro141Leu	missense_variant	2/3	1	NM_001544.5	ENSP00000370147	P2
ICAM4	ENST00000340992.4	c.395-50C>T		intron_variant		1		ENSP00000342114
ICAM4-AS1	ENST00000589379.1	n.1457G>A		non_coding_transcript_exon_variant	1/1
ICAM4	ENST00000393717.2	c.422C>T	p.Pro141Leu	missense_variant	2/2	2		ENSP00000377320	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.422C>T (p.P141L) alteration is located in exon 2 (coding exon 2) of the ICAM4 gene. This alteration results from a C to T substitution at nucleotide position 422, causing the proline (P) at amino acid position 141 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-2.1	N;D
REVEL	Benign	0.11
Sift	Benign	1.0	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.84	P;P
Vest4		0.33
MutPred		0.78		Loss of disorder (P = 0.0909);Loss of disorder (P = 0.0909);
MVP		0.28
ClinPred		0.16	T
GERP RS		1.0
Varity_R		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10398239;