8-27780149-GTT-GT

Variant names:

• chr8-27780149-GT-G
• rs375159544
• NM_001017420.3:c.862-15delT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001017420.3(ESCO2):​c.862-15delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,276,292 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: ESCO2 NM_001017420.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.907
• Publications: 0 publications found

Genes affected

ESCO2 (HGNC:27230): (establishment of sister chromatid cohesion N-acetyltransferase 2) This gene encodes a protein that may have acetyltransferase activity and may be required for the establishment of sister chromatid cohesion during the S phase of mitosis. Mutations in this gene have been associated with Roberts syndrome. [provided by RefSeq, Jul 2008]

ESCO2 Gene-Disease associations (from GenCC):

• Roberts-SC phocomelia syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Roberts syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (679/149158) while in subpopulation AFR AF = 0.0152 (617/40658). AF 95% confidence interval is 0.0142. There are 5 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017420.3. 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
	ESCO2	NM_001017420.3	MANE Select	c.862-15delT		intron	N/A	NP_001017420.1	Q56NI9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESCO2	ENST00000305188.13	TSL:1 MANE Select	c.862-24delT		intron	N/A	ENSP00000306999.8	Q56NI9-1
	ESCO2	ENST00000522378.5	TSL:1	n.861+2981delT		intron	N/A	ENSP00000428928.1	E5RFE4
	ESCO2	ENST00000523910.1	TSL:3	n.661-24delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 676 AN: 149050 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000300

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00391

GnomAD2 exomes AF: 0.00239 AC: 401 AN: 167462 AF XY: 0.00190

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.000647

Gnomad EAS exome AF: 0.000755

Gnomad FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.000870

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00161 AC: 1814 AN: 1127134 Hom.: 5 Cov.: 19 AF XY: 0.00148 AC XY: 844 AN XY: 569656

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

African (AFR) AF: 0.0171 AC: 448 AN: 26124

American (AMR) AF: 0.00191 AC: 74 AN: 38692

Ashkenazi Jewish (ASJ) AF: 0.000323 AC: 7 AN: 21680

East Asian (EAS) AF: 0.000263 AC: 9 AN: 34266

South Asian (SAS) AF: 0.000993 AC: 70 AN: 70468

European-Finnish (FIN) AF: 0.000555 AC: 27 AN: 48614

Middle Eastern (MID) AF: 0.000204 AC: 1 AN: 4894

European-Non Finnish (NFE) AF: 0.00128 AC: 1066 AN: 834830

Other (OTH) AF: 0.00235 AC: 112 AN: 47566

⚠️ 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 AF: 0.00455 AC: 679 AN: 149158 Hom.: 5 Cov.: 33 AF XY: 0.00441 AC XY: 321 AN XY: 72736

African (AFR) AF: 0.0152 AC: 617 AN: 40658

American (AMR) AF: 0.00262 AC: 39 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4694

European-Finnish (FIN) AF: 0.000300 AC: 3 AN: 10014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67080

Other (OTH) AF: 0.00387 AC: 8 AN: 2066

Alfa AF: 0.00414 Hom.: 0

Bravo AF: 0.00530

ClinVar

ClinVar submissions as Germline

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
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375159544; hg19: chr8-27637666;