NM_024009.3:c.-40G>A

Variant names:

• chr1-34781764-G-A
• rs559520550
• NM_024009.3:c.-40G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_024009.3(GJB3):​c.-40G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 152,558 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (0 hom.)
• Consequence: GJB3 NM_024009.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.87
• Publications: 0 publications found

Genes affected

GJB3 (HGNC:4285): (gap junction protein beta 3) 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. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-34781764-G-A is Benign according to our data. Variant chr1-34781764-G-A is described in ClinVar as Benign. ClinVar VariationId is 875774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000184 (28/152284) while in subpopulation SAS AF = 0.00311 (15/4830). AF 95% confidence interval is 0.00191. There are 1 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024009.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	NM_024009.3	MANE Select	c.-40G>A		5_prime_UTR	Exon 1 of 2	NP_076872.1	O75712

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	ENST00000373366.3	TSL:1 MANE Select	c.-40G>A		5_prime_UTR	Exon 1 of 2	ENSP00000362464.2	O75712
	SMIM12	ENST00000426886.1	TSL:1	n.208-63355C>T		intron	N/A	ENSP00000429902.1	E5RH51
	ENSG00000255811	ENST00000542839.1	TSL:5	n.110+6224C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00365 AC: 1 AN: 274 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 196

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00420 AC: 1 AN: 238

Other (OTH) AF: 0.00 AC: 0 AN: 12

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Erythrokeratodermia variabilis et progressiva 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		1.9

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

Other links and lift over

dbSNP: rs559520550; hg19: chr1-35247365; COSMIC: COSV64904540; COSMIC: COSV64904540;