rs913257

chr1-170552235-G-Achr1-170552235-G-Cchr1-170552235-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152281.3(GORAB):c.883G>A(p.Glu295Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,613,706 control chromosomes in the GnomAD database, including 201,261 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20782 hom., cov: 32)
  • Exomes 𝑓: 0.49 (180479 hom.)
• Consequence: GORAB NM_152281.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1499877E-6).
• BP6: Variant 1-170552235-G-A is Benign according to our data. Variant chr1-170552235-G-A is described in ClinVar as [Benign]. Clinvar id is 262629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-170552235-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GORAB	NM_152281.3	c.883G>A	p.Glu295Lys	missense_variant	5/5	ENST00000367763.8
GORAB	NM_001410894.1	c.832G>A	p.Glu278Lys	missense_variant	5/5
GORAB	NM_001320252.2	c.418G>A	p.Glu140Lys	missense_variant	7/7
GORAB	NR_027397.2	n.945G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GORAB	ENST00000367763.8	c.883G>A	p.Glu295Lys	missense_variant	5/5	2	NM_152281.3	P1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78141 AN: 151876 Hom.: 20750 Cov.: 32

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.486

GnomAD3 exomes AF: 0.544 AC: 136688 AN: 251324 Hom.: 39308 AF XY: 0.532 AC XY: 72313 AN XY: 135812

Gnomad AFR exome AF: 0.523

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.416

Gnomad EAS exome AF: 0.909

Gnomad SAS exome AF: 0.497

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.473

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.489 AC: 715334 AN: 1461712 Hom.: 180479 Cov.: 49 AF XY: 0.489 AC XY: 355413 AN XY: 727152

Gnomad4 AFR exome AF: 0.515

Gnomad4 AMR exome AF: 0.656

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.921

Gnomad4 SAS exome AF: 0.495

Gnomad4 FIN exome AF: 0.560

Gnomad4 NFE exome AF: 0.464

Gnomad4 OTH exome AF: 0.498

GnomAD4 genome AF: 0.515 AC: 78226 AN: 151994 Hom.: 20782 Cov.: 32 AF XY: 0.523 AC XY: 38829 AN XY: 74280

Gnomad4 AFR AF: 0.524

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.890

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.491

Alfa AF: 0.479 Hom.: 46298

Bravo AF: 0.520

TwinsUK AF: 0.465 AC: 1726

ALSPAC AF: 0.470 AC: 1811

ESP6500AA AF: 0.531 AC: 2340

ESP6500EA AF: 0.463 AC: 3979

ExAC AF: 0.539 AC: 65464

Asia WGS AF: 0.676 AC: 2348 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Geroderma osteodysplastica Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.98	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.14
Sift	Benign	0.059	T
Sift4G	Uncertain	0.023	D
Polyphen		0.78	P
Vest4		0.073
MPC		0.49
ClinPred		0.027	T
GERP RS		2.6
Varity_R		0.060
gMVP		0.14

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: rs913257; hg19: chr1-170521376; COSMIC: COSV63027816;