chr19-7477222-C-T

Position:

• chr19-7477222-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080662.4(PEX11G):​c.706G>A​(p.Ala236Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PEX11G NM_080662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.419

Genes affected

PEX11G (HGNC:20208): (peroxisomal biogenesis factor 11 gamma) The protein encoded by this gene is a member of the PEX11 family. This family is reported to regulate the number and size of peroxisomes in evolutionarily distant organisms. The protein encoded by this gene may induce clustering of peroxisomes. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

ARHGEF18 (HGNC:17090): (Rho/Rac guanine nucleotide exchange factor 18) Rho GTPases are GTP binding proteins that regulate a wide spectrum of cellular functions. These cellular processes include cytoskeletal rearrangements, gene transcription, cell growth and motility. Activation of Rho GTPases is under the direct control of guanine nucleotide exchange factors (GEFs). The protein encoded by this gene is a guanine nucleotide exchange factor and belongs to the Rho GTPase GEF family. Family members share a common feature, a Dbl (DH) homology domain followed by a pleckstrin (PH) homology domain. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08383706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX11G	NM_080662.4	c.706G>A	p.Ala236Thr	missense_variant	5/5	ENST00000221480.6	NP_542393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX11G	ENST00000221480.6	c.706G>A	p.Ala236Thr	missense_variant	5/5	1	NM_080662.4	ENSP00000221480.1
PEX11G	ENST00000593942.5	c.496G>A	p.Ala166Thr	missense_variant	7/7	5		ENSP00000472216.1
PEX11G	ENST00000593547.1	c.484G>A	p.Ala162Thr	missense_variant	5/5	5		ENSP00000472956.1
PEX11G	ENST00000599519.1	n.508G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369672 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 674768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.34e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.706G>A (p.A236T) alteration is located in exon 5 (coding exon 5) of the PEX11G gene. This alteration results from a G to A substitution at nucleotide position 706, causing the alanine (A) at amino acid position 236 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0070	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.087
Sift	Benign	0.090	T;.
Sift4G	Uncertain	0.017	D;D
Polyphen		0.0010	B;.
Vest4		0.064
MutPred		0.19		Gain of phosphorylation at A236 (P = 0.0509);.;
MVP		0.23
MPC		0.050
ClinPred		0.088	T
GERP RS		-0.81
Varity_R		0.060
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-7542108;