chr3-172762773-A-T

Variant names:

• chr3-172762773-A-T
• rs747123435
• NM_001258315.2:c.972A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258315.2(ECT2):​c.972A>T​(p.Glu324Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ECT2 NM_001258315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

Genes affected

ECT2 (HGNC:3155): (epithelial cell transforming 2) The protein encoded by this gene is a guanine nucleotide exchange factor and transforming protein that is related to Rho-specific exchange factors and yeast cell cycle regulators. The expression of this gene is elevated with the onset of DNA synthesis and remains elevated during G2 and M phases. In situ hybridization analysis showed that expression is at a high level in cells undergoing mitosis in regenerating liver. Thus, this protein is expressed in a cell cycle-dependent manner during liver regeneration, and is thought to have an important role in the regulation of cytokinesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12579006).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258315.2. 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
	ECT2	NM_001258315.2	MANE Select	c.972A>T	p.Glu324Asp	missense	Exon 10 of 25	NP_001245244.1	Q9H8V3-1
	ECT2	NM_001349094.2		c.972A>T	p.Glu324Asp	missense	Exon 11 of 27	NP_001336023.1	Q9H8V3-3
	ECT2	NM_001349095.2		c.972A>T	p.Glu324Asp	missense	Exon 10 of 26	NP_001336024.1	Q9H8V3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECT2	ENST00000392692.8	TSL:1 MANE Select	c.972A>T	p.Glu324Asp	missense	Exon 10 of 25	ENSP00000376457.3	Q9H8V3-1
	ECT2	ENST00000232458.9	TSL:1	c.879A>T	p.Glu293Asp	missense	Exon 9 of 24	ENSP00000232458.5	Q9H8V3-4
	ECT2	ENST00000441497.6	TSL:1	c.879A>T	p.Glu293Asp	missense	Exon 8 of 23	ENSP00000412259.2	Q9H8V3-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249498 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460544 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726476

⚠️ 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: 33426

American (AMR) AF: 0.0000899 AC: 4 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111586

Other (OTH) AF: 0.00 AC: 0 AN: 60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00180467), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

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
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.20
Sift	Benign	0.57	T
Sift4G	Benign	0.60	T
Polyphen		0.014	B
Vest4		0.34
MutPred		0.40		Loss of methylation at K296 (P = 0.074)
MVP		0.87
MPC		0.39
ClinPred		0.20	T
GERP RS		4.7
PromoterAI		-0.00060	Neutral
Varity_R		0.21
gMVP		0.33
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs747123435; hg19: chr3-172480563;