6-121446879-T-C

Position:

• chr6-121446879-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000165.5(GJA1):​c.32T>C​(p.Leu11Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L11I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 21) in uniprot entity CXA1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000165.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GJA1. . Gene score misZ 1.2784 (greater than the threshold 3.09). Trascript score misZ 3.3775 (greater than threshold 3.09). GenCC has associacion of gene with craniometaphyseal dysplasia, autosomal recessive, Hallermann-Streiff syndrome, syndactyly type 3, oculodentodigital dysplasia, nonsyndromic genetic hearing loss, hypoplastic left heart syndrome 1, autosomal dominant palmoplantar keratoderma and congenital alopecia, oculodentodigital dysplasia, autosomal recessive, craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva 3, erythrokeratodermia variabilis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 6-121446879-T-C is Pathogenic according to our data. Variant chr6-121446879-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16993.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA1	NM_000165.5	c.32T>C	p.Leu11Pro	missense_variant	2/2	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.32T>C	p.Leu11Pro	missense_variant	2/2	1	NM_000165.5	ENSP00000282561	P1
GJA1	ENST00000647564.1	c.32T>C	p.Leu11Pro	missense_variant	2/2			ENSP00000497565	P1
GJA1	ENST00000649003.1	c.32T>C	p.Leu11Pro	missense_variant	2/2			ENSP00000497283	P1
GJA1	ENST00000650427.1	c.32T>C	p.Leu11Pro	missense_variant	2/2			ENSP00000497367	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oculodentodigital dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;.;.;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	.;.;D;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.98
MutPred		0.98		Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);Gain of disorder (P = 0.014);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.97
gMVP		1.0

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: rs121912969; hg19: chr6-121768025;