1-6820181-A-G

Position:

• chr1-6820181-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015215.4(CAMTA1):​c.46A>G​(p.Ser16Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000738 in 1,354,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CAMTA1 NM_015215.4 missense, splice_region
• Scores: Splicing: ADA: 0.6472
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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]

CAMTA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3161853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMTA1	NM_015215.4	c.46A>G	p.Ser16Gly	missense_variant, splice_region_variant	2/23	ENST00000303635.12	NP_056030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMTA1	ENST00000303635.12	c.46A>G	p.Ser16Gly	missense_variant, splice_region_variant	2/23	1	NM_015215.4	ENSP00000306522.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354566 Hom.: 0 Cov.: 20 AF XY: 0.00000147 AC XY: 1 AN XY: 680032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.86e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 21, 2024

Variant summary: CAMTA1 c.46A>G (p.Ser16Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248850 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.46A>G in individuals affected with Nonprogressive Cerebellar Atxia With Intellectual Disability and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0093	T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.33	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.090	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.039	D;T;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.92	P;.;.
Vest4		0.47
MutPred		0.18		Loss of phosphorylation at S16 (P = 0.039);Loss of phosphorylation at S16 (P = 0.039);Loss of phosphorylation at S16 (P = 0.039);
MVP		0.62
MPC		0.60
ClinPred		0.72	D
GERP RS		5.1
Varity_R		0.15
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.65
dbscSNV1_RF	Benign	0.52
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6880241;