19-10287605-T-C

Position:

• chr19-10287605-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001544.5(ICAM4):​c.464T>C​(p.Val155Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 2.19

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICAM4	NM_001544.5	c.464T>C	p.Val155Ala	missense_variant	2/3	ENST00000380770.5	NP_001535.1
ICAM4	NM_001039132.3	c.395-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001034221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICAM4	ENST00000380770.5	c.464T>C	p.Val155Ala	missense_variant	2/3	1	NM_001544.5	ENSP00000370147	P2
ICAM4	ENST00000340992.4	c.395-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000342114
ICAM4-AS1	ENST00000589379.1	n.1415A>G		non_coding_transcript_exon_variant	1/1
ICAM4	ENST00000393717.2	c.464T>C	p.Val155Ala	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

Oct 13, 2023

The c.464T>C (p.V155A) alteration is located in exon 2 (coding exon 2) of the ICAM4 gene. This alteration results from a T to C substitution at nucleotide position 464, causing the valine (V) at amino acid position 155 to be replaced by an alanine (A). 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;N;N
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.23	B;B
Vest4		0.39
MutPred		0.86		Loss of stability (P = 0.162);Loss of stability (P = 0.162);
MVP		0.14
ClinPred		0.67	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr19-10398281;