Genetic Variant NM_138961.3:c.731-9C>A (chr11-124754349-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138961.3(ESAM):c.731-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,613,680 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 104 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 78 hom. )

Consequence

ESAM
NM_138961.3 intron

Scores

Splicing: ADA: 0.0003851

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.351

Publications

1 publications found

Variant links:

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

ESAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-124754349-G-T is Benign according to our data. Variant chr11-124754349-G-T is described in ClinVar as Benign. ClinVar VariationId is 781240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

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>A		intron	N/A	NP_620411.2	Q96AP7-1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2803

AN:

152140

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0637

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00500

AC:

1251

AN:

250074

AF XY:

0.00368

show subpopulations

Gnomad AFR exome

AF:

0.0638

Gnomad AMR exome

AF:

0.00412

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000513

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00220

AC:

3212

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1387

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.0661

AC:

2212

AN:

33472

American (AMR)

AF:

0.00461

AC:

206

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000151

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000416

AC:

463

AN:

1111828

Other (OTH)

AF:

0.00477

AC:

288

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

156

312

467

623

779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0184

AC:

2809

AN:

152258

Hom.:

104

Cov.:

AF XY:

0.0175

AC XY:

1302

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0637

AC:

2643

AN:

41518

American (AMR)

AF:

0.00673

AC:

103

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68030

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00971

Hom.:

Bravo

AF:

0.0212

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.74

(source)

DANN

Benign

0.75

PhyloP100

-0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.062

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over