rs529052852

Variant names:

• chr7-51025174-C-T
• rs529052852
• NM_015198.5:c.3703G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015198.5(COBL):​c.3703G>A​(p.Ala1235Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000081 in 1,382,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: COBL NM_015198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 1 publications found

Genes affected

COBL (HGNC:22199): (cordon-bleu WH2 repeat protein) This gene encodes a protein that contains WH2 domains (WASP, Wiskott-Aldrich syndrome protein, homology domain-2) that interact with actin. The encoded actin regulator protein is required for growth and assembly of brush border microvilli that play a role in maintaining intestinal homeostasis. A similar protein in mouse functions in midbrain neural tube closure. A pseudogene of this gene is located on chromosome X. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041022837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015198.5. 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
	COBL	NM_015198.5	MANE Select	c.3703G>A	p.Ala1235Thr	missense	Exon 12 of 13	NP_056013.2
	COBL	NM_001410881.1		c.3949G>A	p.Ala1317Thr	missense	Exon 14 of 15	NP_001397810.1	O75128-2
	COBL	NM_001287436.3		c.3733G>A	p.Ala1245Thr	missense	Exon 13 of 14	NP_001274365.1	O75128-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COBL	ENST00000265136.12	TSL:1 MANE Select	c.3703G>A	p.Ala1235Thr	missense	Exon 12 of 13	ENSP00000265136.7	O75128-1
	COBL	ENST00000431948.6	TSL:1	c.3949G>A	p.Ala1317Thr	missense	Exon 14 of 15	ENSP00000413498.2	O75128-2
	COBL	ENST00000395542.6	TSL:1	c.3733G>A	p.Ala1245Thr	missense	Exon 13 of 14	ENSP00000378912.3	O75128-7

Frequencies

GnomAD3 genomes AF: 0.0000867 AC: 12 AN: 138330 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.000140

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 249482 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000804 AC: 100 AN: 1244314 Hom.: 0 Cov.: 38 AF XY: 0.0000973 AC XY: 60 AN XY: 616728

African (AFR) AF: 0.00 AC: 0 AN: 27126

American (AMR) AF: 0.000550 AC: 21 AN: 38162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18048

East Asian (EAS) AF: 0.00 AC: 0 AN: 19452

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3026

European-Non Finnish (NFE) AF: 0.0000771 AC: 75 AN: 972322

Other (OTH) AF: 0.0000218 AC: 1 AN: 45910

GnomAD4 genome AF: 0.0000867 AC: 12 AN: 138422 Hom.: 0 Cov.: 30 AF XY: 0.0000900 AC XY: 6 AN XY: 66698

African (AFR) AF: 0.0000262 AC: 1 AN: 38164

American (AMR) AF: 0.00 AC: 0 AN: 13588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 3924

South Asian (SAS) AF: 0.00 AC: 0 AN: 3826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8068

Middle Eastern (MID) AF: 0.00719 AC: 2 AN: 278

European-Non Finnish (NFE) AF: 0.000140 AC: 9 AN: 64428

Other (OTH) AF: 0.00 AC: 0 AN: 1980

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.4
DANN	Benign	0.95
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.049
Sift	Benign	0.042	D
Sift4G	Benign	0.17	T
Polyphen		0.25	B
Vest4		0.049
MVP		0.17
MPC		0.076
ClinPred		0.020	T
GERP RS		1.8
Varity_R		0.028
gMVP		0.11
Mutation Taster		=99/1	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: rs529052852; hg19: chr7-51092871; COSMIC: COSV54360187; COSMIC: COSV54360187;