19-10287586-T-C

Variant names:

• chr19-10287586-T-C
• rs2040127607
• NM_001544.5:c.445T>C

Variant summary

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

The NM_001544.5(ICAM4):​c.445T>C​(p.Tyr149His) 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. 12/18 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: 2.43

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=0.3183301).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM4	NM_001544.5	c.445T>C	p.Tyr149His	missense_variant	Exon 2 of 3	ENST00000380770.5	NP_001535.1
ICAM4	NM_001039132.3	c.395-27T>C		intron_variant	Intron 1 of 2		NP_001034221.1
ICAM4-AS1	NR_186335.1	n.1434A>G		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM4	ENST00000380770.5	c.445T>C	p.Tyr149His	missense_variant	Exon 2 of 3	1	NM_001544.5	ENSP00000370147.2
ICAM4	ENST00000340992.4	c.395-27T>C		intron_variant	Intron 1 of 2	1		ENSP00000342114.3
ICAM4	ENST00000393717.2	c.445T>C	p.Tyr149His	missense_variant	Exon 2 of 2	2		ENSP00000377320.1
ICAM4-AS1	ENST00000589379.1	n.1434A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

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

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.445T>C (p.Y149H) 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 445, causing the tyrosine (Y) at amino acid position 149 to be replaced by a histidine (H). 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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;L
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.12	B;B
Vest4		0.49
MutPred		0.72		Gain of disorder (P = 0.036);Gain of disorder (P = 0.036);
MVP		0.17
ClinPred		0.33	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2040127607; hg19: chr19-10398262;