chr1-34761404-CT-C

Variant names:

• chr1-34761404-CT-C
• rs139849901
• NM_153212.3:c.153delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_153212.3(GJB4):​c.153delT​(p.Phe51LeufsTer57) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,613,820 control chromosomes in the GnomAD database, including 148 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (77 hom.)
• Consequence: GJB4 NM_153212.3 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.97
• 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]

ENSG00000255811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• BP6: Variant 1-34761404-CT-C is Benign according to our data. Variant chr1-34761404-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB4	NM_153212.3	MANE Select	c.153delT	p.Phe51LeufsTer57	frameshift	Exon 2 of 2	NP_694944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB4	ENST00000339480.3	TSL:2 MANE Select	c.153delT	p.Phe51LeufsTer57	frameshift	Exon 2 of 2	ENSP00000345868.1
	SMIM12	ENST00000426886.1	TSL:1	n.208-42996delA		intron	N/A	ENSP00000429902.1
	ENSG00000255811	ENST00000542839.1	TSL:5	n.*21delA		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2464 AN: 151838 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00408 AC: 1022 AN: 250726 AF XY: 0.00299

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00169 AC: 2471 AN: 1461862 Hom.: 77 Cov.: 31 AF XY: 0.00145 AC XY: 1057 AN XY: 727228

African (AFR) AF: 0.0591 AC: 1978 AN: 33480

American (AMR) AF: 0.00291 AC: 130 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111990

Other (OTH) AF: 0.00391 AC: 236 AN: 60394

GnomAD4 genome AF: 0.0162 AC: 2468 AN: 151958 Hom.: 71 Cov.: 32 AF XY: 0.0161 AC XY: 1197 AN XY: 74284

African (AFR) AF: 0.0568 AC: 2360 AN: 41548

American (AMR) AF: 0.00419 AC: 64 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10544

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67802

Other (OTH) AF: 0.0137 AC: 29 AN: 2110

Alfa AF: 0.00764 Hom.: 6

Bravo AF: 0.0184

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 30, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Erythrokeratodermia variabilis et progressiva 2 Benign:1

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=156/44	polymorphism

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: rs139849901; hg19: chr1-35227005;