1-38875334-G-T

Position:

• chr1-38875334-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030772.5(GJA9):​c.765C>A​(p.Phe255Leu) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA9 NM_030772.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.968

Genes affected

GJA9 (HGNC:19155): (gap junction protein alpha 9) Connexins, such as GJA9, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

ENSG00000274944 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08459929).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA9	NM_030772.5	c.765C>A	p.Phe255Leu	missense_variant	2/2	ENST00000357771.5	NP_110399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA9	ENST00000357771.5	c.765C>A	p.Phe255Leu	missense_variant	2/2	1	NM_030772.5	ENSP00000350415.3
ENSG00000274944	ENST00000621281.1	c.37-2244C>A		intron_variant		2		ENSP00000479064.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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 03, 2023

The c.765C>A (p.F255L) alteration is located in exon 2 (coding exon 1) of the GJA9 gene. This alteration results from a C to A substitution at nucleotide position 765, causing the phenylalanine (F) at amino acid position 255 to be replaced by a leucine (L). 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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Uncertain	0.080	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0	B;B
Vest4		0.084
MutPred		0.26		Gain of MoRF binding (P = 0.1081);Gain of MoRF binding (P = 0.1081);
MVP		0.73
MPC		0.082
ClinPred		0.10	T
GERP RS		3.6
Varity_R		0.14
gMVP		0.39

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: chr1-39341006;