12-1028498-G-A

Position:

• chr12-1028498-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178040.4(ERC1):​c.595G>A​(p.Ala199Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERC1 NM_178040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

Genes affected

ERC1 (HGNC:17072): (ELKS/RAB6-interacting/CAST family member 1) The protein encoded by this gene is a member of a family of RIM-binding proteins. RIMs are active zone proteins that regulate neurotransmitter release. This gene has been found fused to the receptor-type tyrosine kinase gene RET by gene rearrangement due to the translocation t(10;12)(q11;p13) in thyroid papillary carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ERC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERC1	NM_178040.4	c.595G>A	p.Ala199Thr	missense_variant	2/19	ENST00000360905.9	NP_829884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERC1	ENST00000360905.9	c.595G>A	p.Ala199Thr	missense_variant	2/19	1	NM_178040.4	ENSP00000354158.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Ambry Genetics

May 02, 2024

The c.595G>A (p.A199T) alteration is located in exon 1 (coding exon 1) of the ERC1 gene. This alteration results from a G to A substitution at nucleotide position 595, causing the alanine (A) at amino acid position 199 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;.;.;T;.;.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Uncertain	2.4	M;.;.;M;M;M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;N;.;N;.;N;.;N
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;D;.;D;.;D;.;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T
Polyphen		0.99	D;.;.;P;.;D;P;.
Vest4		0.81
MutPred		0.45		Gain of phosphorylation at A199 (P = 0.0051);Gain of phosphorylation at A199 (P = 0.0051);.;Gain of phosphorylation at A199 (P = 0.0051);Gain of phosphorylation at A199 (P = 0.0051);Gain of phosphorylation at A199 (P = 0.0051);Gain of phosphorylation at A199 (P = 0.0051);Gain of phosphorylation at A199 (P = 0.0051);
MVP		0.73
MPC		1.1
ClinPred		0.89	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.58

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-1137664;