Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The ENST00000367763.8(GORAB):c.658G>C(p.Ala220Pro) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A220T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GORAB
ENST00000367763.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.36

Publications

4 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

geroderma osteodysplastica
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

GORAB links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 1-170544841-G-C is Pathogenic according to our data. Variant chr1-170544841-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 218115.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367763.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GORAB	NM_152281.3	MANE Select	c.658G>C	p.Ala220Pro	missense	Exon 4 of 5	NP_689494.3
GORAB	NM_001410894.1		c.607G>C	p.Ala203Pro	missense	Exon 4 of 5	NP_001397823.1
GORAB	NM_001146039.2		c.658G>C	p.Ala220Pro	missense	Exon 4 of 4	NP_001139511.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GORAB	ENST00000367763.8	TSL:2 MANE Select	c.658G>C	p.Ala220Pro	missense	Exon 4 of 5	ENSP00000356737.4
GORAB	ENST00000367762.2	TSL:1	c.658G>C	p.Ala220Pro	missense	Exon 4 of 4	ENSP00000356736.2
GORAB	ENST00000475113.1	TSL:1	n.202G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Geroderma osteodysplastica (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.4

PhyloP100

9.4

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.98

MutPred

0.78

Gain of loop (P = 0.0051)

MVP

0.97

MPC

0.68

ClinPred

0.99

GERP RS

5.8

Varity_R

0.92

gMVP

0.80

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over