1-170532186-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152281.3(GORAB):c.-38G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GORAB NM_152281.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00600

Genes affected

GORAB (HGNC:25676): (golgin, RAB6 interacting) This gene encodes a member of the golgin family, a group of coiled-coil proteins localized to the Golgi. The encoded protein may function in the secretory pathway. The encoded protein, which also localizes to the cytoplasm, was identified by interactions with the N-terminal kinase-like protein, and thus it may function in mitosis. Mutations in this gene have been associated with geroderma osteodysplastica. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

GORAB-AS1 (HGNC:54051): (GORAB antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41008556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GORAB	NM_152281.3	c.-38G>T		5_prime_UTR_variant	1/5	ENST00000367763.8
GORAB-AS1	NR_125958.1	n.162+262C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GORAB	ENST00000367763.8	c.-38G>T		5_prime_UTR_variant	1/5	2	NM_152281.3	P1
GORAB-AS1	ENST00000456083.5	n.200+262C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461504 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727040

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2022

This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 13 of the GORAB protein (p.Arg13Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GORAB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	7.0
Dann	Benign	0.97
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.81	P;D
Vest4		0.49
MutPred		0.35		Loss of MoRF binding (P = 0.0025);Loss of MoRF binding (P = 0.0025);
MVP		0.69
MPC		0.72
ClinPred		0.35	T
GERP RS		0.84
Varity_R		0.072
gMVP		0.10

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: rs1648714458; hg19: chr1-170501327;