11-124754349-G-A

Variant names:

• chr11-124754349-G-A
• rs77048222
• NM_138961.3:c.731-9C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138961.3(ESAM):​c.731-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ESAM NM_138961.3 intron
• Scores: Splicing: ADA: 0.00004970
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138961.3. 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
	ESAM	NM_138961.3	MANE Select	c.731-9C>T		intron	N/A	NP_620411.2	Q96AP7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESAM	ENST00000278927.10	TSL:1 MANE Select	c.731-9C>T		intron	N/A	ENSP00000278927.5	Q96AP7-1
	ESAM	ENST00000417453.5	TSL:1	n.*4-9C>T		intron	N/A	ENSP00000389235.1	F8WDW9
	ESAM	ENST00000906451.1		c.848-9C>T		intron	N/A	ENSP00000576510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461426 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727002

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111828

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.85
DANN	Benign	0.65
PhyloP100		-0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0
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: rs77048222; hg19: chr11-124624245;