chr19-10334710-A-T

Variant names:

• chr19-10334710-A-T
• rs1418742573
• NM_002162.5:c.1010T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001395376.1(ICAM3):​c.2T>A​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ICAM3 NM_001395376.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.15
• Publications: 0 publications found

Genes affected

ICAM3 (HGNC:5346): (intercellular adhesion molecule 3) The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycoproteins, contain 2-9 immunoglobulin-like C2-type domains, and bind to the leukocyte adhesion LFA-1 protein. This protein is constitutively and abundantly expressed by all leucocytes and may be the most important ligand for LFA-1 in the initiation of the immune response. It functions not only as an adhesion molecule, but also as a potent signalling molecule. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

ENSG00000274425 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 141 codons. Genomic position: 10334172. Lost 0.662 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395376.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM3	NM_002162.5	MANE Select	c.1010T>A	p.Met337Lys	missense	Exon 5 of 7	NP_002153.2	P32942
	ICAM3	NM_001395376.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 3	NP_001382305.1	A0A9L9PXS1
	ICAM3	NM_001320606.2		c.779T>A	p.Met260Lys	missense	Exon 5 of 7	NP_001307535.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM3	ENST00000160262.10	TSL:1 MANE Select	c.1010T>A	p.Met337Lys	missense	Exon 5 of 7	ENSP00000160262.3	P32942
	ICAM3	ENST00000589261.5	TSL:1	n.1312T>A		non_coding_transcript_exon	Exon 5 of 7
	ICAM3	ENST00000706691.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 3	ENSP00000516505.1	A0A9L9PXS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.7
DANN	Benign	0.73
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.014
Sift	Benign	0.47	T
Sift4G	Benign	0.86	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.53		Gain of ubiquitination at M337 (P = 0.0138)
MVP		0.030
MPC		0.63
ClinPred		0.035	T
GERP RS		-5.8
PromoterAI		0.015	Neutral
Varity_R		0.17
gMVP		0.57
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1418742573; hg19: chr19-10445386;