1-6825207-T-G

Position:

• chr1-6825207-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_015215.4(CAMTA1):​c.231T>G​(p.Asn77Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N77D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAMTA1 NM_015215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

Genes affected

CAMTA1 (HGNC:18806): (calmodulin binding transcription activator 1) The protein encoded by this gene contains a CG1 DNA-binding domain, a transcription factor immunoglobulin domain, ankyrin repeats, and calmodulin-binding IQ motifs. The encoded protein is thought to be a transcription factor and may be a tumor suppressor. However, a translocation event is sometimes observed between this gene and the WWTR1 gene, with the resulting WWTR1-CAMTA1 oncoprotein leading to epithelioid hemangioendothelioma, a malignant vascular cancer. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a DNA_binding_region CG-1 (size 125) in uniprot entity CMTA1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_015215.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAMTA1. . Gene score misZ 3.2619 (greater than the threshold 3.09). Trascript score misZ 4.755 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar dysfunction with variable cognitive and behavioral abnormalities.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMTA1	NM_015215.4	c.231T>G	p.Asn77Lys	missense_variant	3/23	ENST00000303635.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMTA1	ENST00000303635.12	c.231T>G	p.Asn77Lys	missense_variant	3/23	1	NM_015215.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.037	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.89
MutPred		0.53		Gain of methylation at N77 (P = 0.0043);Gain of methylation at N77 (P = 0.0043);Gain of methylation at N77 (P = 0.0043);.;
MVP		0.64
MPC		0.78
ClinPred		0.94	D
GERP RS		2.3
Varity_R		0.26
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6885267;