NM_001544.5:c.581C>A

Variant names:

• chr19-10287722-C-A
• NM_001544.5:c.581C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001544.5(ICAM4):​c.581C>A​(p.Thr194Asn) 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. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICAM4 NM_001544.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21807736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM4	NM_001544.5	c.581C>A	p.Thr194Asn	missense_variant	Exon 2 of 3	ENST00000380770.5	NP_001535.1
ICAM4	NM_001039132.3	c.504C>A	p.Asp168Glu	missense_variant	Exon 2 of 3		NP_001034221.1
ICAM4-AS1	NR_186335.1	n.1298G>T		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.581C>A	p.Thr194Asn	missense_variant	Exon 2 of 3	1	NM_001544.5	ENSP00000370147.2
ICAM4	ENST00000340992.4	c.504C>A	p.Asp168Glu	missense_variant	Exon 2 of 3	1		ENSP00000342114.3
ICAM4	ENST00000393717.2	c.581C>A	p.Thr194Asn	missense_variant	Exon 2 of 2	2		ENSP00000377320.1
ICAM4-AS1	ENST00000589379.1	n.1298G>T		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

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.581C>A (p.T194N) alteration is located in exon 2 (coding exon 2) of the ICAM4 gene. This alteration results from a C to A substitution at nucleotide position 581, causing the threonine (T) at amino acid position 194 to be replaced by an asparagine (N). 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	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.066
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.23
MutPred		0.32		Gain of catalytic residue at D168 (P = 0.1154);
MVP		0.092
MPC		0.92
ClinPred		0.90	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10398398;