1-100724706-C-A

Variant names:

• chr1-100724706-C-A
• rs754644270
• NM_001078.4:c.744C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001078.4(VCAM1):​c.744C>A​(p.Ser248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S248S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VCAM1 NM_001078.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.996
• Publications: 0 publications found

Genes affected

VCAM1 (HGNC:12663): (vascular cell adhesion molecule 1) This gene is a member of the Ig superfamily and encodes a cell surface sialoglycoprotein expressed by cytokine-activated endothelium. This type I membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and may play a role in the development of artherosclerosis and rheumatoid arthritis. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Dec 2010]

ENSG00000299357 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001078.4. 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
	VCAM1	NM_001078.4	MANE Select	c.744C>A	p.Ser248Arg	missense	Exon 4 of 9	NP_001069.1	P19320-1
	VCAM1	NM_001199834.2		c.558C>A	p.Ser186Arg	missense	Exon 4 of 9	NP_001186763.1	P19320-3
	VCAM1	NM_080682.3		c.744C>A	p.Ser248Arg	missense	Exon 4 of 8	NP_542413.1	P19320-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAM1	ENST00000294728.7	TSL:1 MANE Select	c.744C>A	p.Ser248Arg	missense	Exon 4 of 9	ENSP00000294728.2	P19320-1
	VCAM1	ENST00000347652.6	TSL:1	c.744C>A	p.Ser248Arg	missense	Exon 4 of 8	ENSP00000304611.2	P19320-2
	VCAM1	ENST00000855907.1		c.744C>A	p.Ser248Arg	missense	Exon 4 of 9	ENSP00000525966.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460982 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726796

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111500

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.071	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-1.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.81
MutPred		0.74		Loss of glycosylation at T245 (P = 0.0598)
MVP		0.50
MPC		0.70
ClinPred		0.93	D
GERP RS		-3.5
Varity_R		0.60
gMVP		0.89
Mutation Taster		=64/36	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: rs754644270; hg19: chr1-101190262;