chr1-170544841-G-C

Position:

• chr1-170544841-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_152281.3(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 NM_152281.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.36

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 218115.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-170544841-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GORAB	NM_152281.3	c.658G>C	p.Ala220Pro	missense_variant	4/5	ENST00000367763.8	NP_689494.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GORAB	ENST00000367763.8	c.658G>C	p.Ala220Pro	missense_variant	4/5	2	NM_152281.3	ENSP00000356737.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Geroderma osteodysplastica Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2009	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.78		Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);
MVP		0.97
MPC		0.68
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.80

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: rs183596463; hg19: chr1-170513982;