chr1-170539515-G-A

Variant names:

• chr1-170539515-G-A
• rs119455951
• NM_152281.3:c.367G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152281.3(GORAB):​c.367G>A​(p.Glu123Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E123G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GORAB NM_152281.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16023451).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152281.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GORAB	NM_152281.3	MANE Select	c.367G>A	p.Glu123Lys	missense	Exon 2 of 5	NP_689494.3
	GORAB	NM_001410894.1		c.316G>A	p.Glu106Lys	missense	Exon 2 of 5	NP_001397823.1
	GORAB	NM_001146039.2		c.367G>A	p.Glu123Lys	missense	Exon 2 of 4	NP_001139511.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GORAB	ENST00000367763.8	TSL:2 MANE Select	c.367G>A	p.Glu123Lys	missense	Exon 2 of 5	ENSP00000356737.4
	GORAB	ENST00000367762.2	TSL:1	c.367G>A	p.Glu123Lys	missense	Exon 2 of 4	ENSP00000356736.2
	GORAB	ENST00000498166.6	TSL:1	n.*361G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000473336.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.090
Sift	Benign	0.26	T
Sift4G	Benign	0.16	T
Polyphen		0.0070	B
Vest4		0.28
MutPred		0.24		Gain of ubiquitination at E148 (P = 0.0025)
MVP		0.67
MPC		0.18
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.072
gMVP		0.20
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs119455951; hg19: chr1-170508656; COSMIC: COSV108208221;