8-27780149-GTT-GT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Roberts syndrome

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

ACMG classification

Our verdict: Benign. The variant received -8 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.
• 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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs375159544;

hg19: chr8-27637666;