NM_153212.3:c.-322-278T>C

Variant names:

• chr1-34760655-T-C
• rs1998177
• NM_153212.3:c.-322-278T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_153212.3(GJB4):​c.-322-278T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 152,068 control chromosomes in the GnomAD database, including 21,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (21497 hom., cov: 32)
• Consequence: GJB4 NM_153212.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.737
• Publications: 3 publications found

Genes affected

GJB4 (HGNC:4286): (gap junction protein beta 4) This gene encodes a transmembrane connexin protein that is a component of gap junctions. Mutations in this gene have been associated with erythrokeratodermia variabilis, progressive symmetric erythrokeratoderma and hearing impairment. [provided by RefSeq, Dec 2009]

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-34760655-T-C is Benign according to our data. Variant chr1-34760655-T-C is described in ClinVar as Benign. ClinVar VariationId is 1247767.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153212.3. 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
	GJB4	NM_153212.3	MANE Select	c.-322-278T>C		intron	N/A	NP_694944.1	Q9NTQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB4	ENST00000339480.3	TSL:2 MANE Select	c.-322-278T>C		intron	N/A	ENSP00000345868.1	Q9NTQ9
	SMIM12	ENST00000426886.1	TSL:1	n.208-42246A>G		intron	N/A	ENSP00000429902.1	E5RH51
	GJB4	ENST00000919353.1		c.-322-278T>C		intron	N/A	ENSP00000589412.1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76370 AN: 151950 Hom.: 21461 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.480

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

GnomAD4 genome AF: 0.503 AC: 76457 AN: 152068 Hom.: 21497 Cov.: 32 AF XY: 0.499 AC XY: 37059 AN XY: 74338

African (AFR) AF: 0.771 AC: 31966 AN: 41486

American (AMR) AF: 0.415 AC: 6343 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1414 AN: 3468

East Asian (EAS) AF: 0.544 AC: 2801 AN: 5152

South Asian (SAS) AF: 0.418 AC: 2012 AN: 4816

European-Finnish (FIN) AF: 0.337 AC: 3563 AN: 10588

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26748 AN: 67956

Other (OTH) AF: 0.476 AC: 1002 AN: 2104

Alfa AF: 0.468 Hom.: 2740

Bravo AF: 0.522

Asia WGS AF: 0.460 AC: 1600 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.97
DANN	Benign	0.43
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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: rs1998177; hg19: chr1-35226256; COSMIC: COSV58355769; COSMIC: COSV58355769;