11-124762092-A-C

Position:

• chr11-124762092-A-C

Variant summary

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

The NM_138961.3(ESAM):​c.63T>G​(p.Ser21Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ESAM NM_138961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.138

Genes affected

ESAM (HGNC:17474): (endothelial cell adhesion molecule) Enables cell-cell adhesion mediator activity. Involved in several processes, including bicellular tight junction assembly; cell-cell adhesion; and regulation of actin cytoskeleton organization. Located in cell-cell junction and plasma membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ESAM-AS1 (HGNC:55558): (ESAM 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=0.1955207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESAM	NM_138961.3	c.63T>G	p.Ser21Arg	missense_variant	1/7	ENST00000278927.10	NP_620411.2
ESAM-AS1	NR_120577.1	n.281-2637A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESAM	ENST00000278927.10	c.63T>G	p.Ser21Arg	missense_variant	1/7	1	NM_138961.3	ENSP00000278927	P1
ESAM-AS1	ENST00000504932.2	n.286-2637A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

May 18, 2023

The c.63T>G (p.S21R) alteration is located in exon 1 (coding exon 1) of the ESAM gene. This alteration results from a T to G substitution at nucleotide position 63, causing the serine (S) at amino acid position 21 to be replaced by an arginine (R). 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	0.64
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.036	D;D;D
Sift4G	Benign	0.13	.;T;.
Polyphen		0.84	.;P;.
Vest4		0.69
MutPred		0.48		Gain of methylation at S21 (P = 0.0284);Gain of methylation at S21 (P = 0.0284);Gain of methylation at S21 (P = 0.0284);
MVP		0.73
MPC		0.19
ClinPred		0.90	D
GERP RS		-0.027
Varity_R		0.34
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs1226752742; hg19: chr11-124631988;