1-38875089-C-T

Variant names:

• chr1-38875089-C-T
• rs142530971
• NM_030772.5:c.1010G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_030772.5(GJA9):​c.1010G>A​(p.Ser337Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,614,092 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: GJA9 NM_030772.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.517

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:):

RRAGC-DT (HGNC:55793): (RRAGC divergent transcript)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004453361).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA9	NM_030772.5	c.1010G>A	p.Ser337Asn	missense_variant	Exon 2 of 2	ENST00000357771.5	NP_110399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA9	ENST00000357771.5	c.1010G>A	p.Ser337Asn	missense_variant	Exon 2 of 2	1	NM_030772.5	ENSP00000350415.3
ENSG00000274944	ENST00000621281.1	c.37-1999G>A		intron_variant	Intron 1 of 4	2		ENSP00000479064.1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000613 AC: 154 AN: 251272 Hom.: 1 AF XY: 0.000589 AC XY: 80 AN XY: 135862

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000648 AC: 948 AN: 1461852 Hom.: 4 Cov.: 35 AF XY: 0.000701 AC XY: 510 AN XY: 727224

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000528

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74424

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000947 Hom.: 1

Bravo AF: 0.000525

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1010G>A (p.S337N) alteration is located in exon 2 (coding exon 1) of the GJA9 gene. This alteration results from a G to A substitution at nucleotide position 1010, causing the serine (S) at amino acid position 337 to be replaced by an asparagine (N). 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	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.73
DANN	Benign	0.73
DEOGEN2	Benign	0.0052	T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Uncertain	0.064	D
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.21
Sift	Benign	0.92	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	B;B
Vest4		0.040
MVP		0.099
MPC		0.067
ClinPred		0.0055	T
GERP RS		2.0
Varity_R		0.043
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs142530971; hg19: chr1-39340761;