6-121435925-T-G

Position:

• chr6-121435925-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000165.5(GJA1):​c.-17+93T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 152,192 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (98 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GJA1 NM_000165.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.445

Genes affected

GJA1 (HGNC:4274): (gap junction protein alpha 1) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-121435925-T-G is Benign according to our data. Variant chr6-121435925-T-G is described in ClinVar as [Benign]. Clinvar id is 1288826.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4663/152192) while in subpopulation NFE AF= 0.0477 (3242/67998). AF 95% confidence interval is 0.0463. There are 98 homozygotes in gnomad4. There are 2257 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 98 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA1	NM_000165.5	c.-17+93T>G		intron_variant		ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.-17+93T>G		intron_variant		1	NM_000165.5	ENSP00000282561	P1
GJA1	ENST00000649003.1	c.-17+265T>G		intron_variant				ENSP00000497283	P1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4663 AN: 152074 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00780

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0322

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0306 AC: 4663 AN: 152192 Hom.: 98 Cov.: 32 AF XY: 0.0303 AC XY: 2257 AN XY: 74416

Gnomad4 AFR AF: 0.00777

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0529

Gnomad4 NFE AF: 0.0477

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0469 Hom.: 31

Bravo AF: 0.0260

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.68

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: rs34726392; hg19: chr6-121757071;