15-44289220-A-G

Variant names:

• chr15-44289220-A-G
• rs1003547108
• NM_138423.4:c.191A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138423.4(GOLM2):​c.191A>G​(p.Glu64Gly) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GOLM2 NM_138423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

Genes affected

GOLM2 (HGNC:24892): (golgi membrane protein 2) The increased expression level of this gene is associated with HER-2/neu proto-oncogene overexpression. Amplification and resulting overexpression of this proto-oncogene are found in approximately 30% of human breast and 20% of human ovarian cancers. Alternatively spliced variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOLM2	NM_138423.4	c.191A>G	p.Glu64Gly	missense_variant	Exon 1 of 10	ENST00000299957.11	NP_612432.2
GOLM2	NM_177974.3	c.191A>G	p.Glu64Gly	missense_variant	Exon 1 of 9		NP_816929.1
GOLM2	NR_157849.2	n.502A>G		non_coding_transcript_exon_variant	Exon 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOLM2	ENST00000299957.11	c.191A>G	p.Glu64Gly	missense_variant	Exon 1 of 10	1	NM_138423.4	ENSP00000299957.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191A>G (p.E64G) alteration is located in exon 1 (coding exon 1) of the CASC4 gene. This alteration results from a A to G substitution at nucleotide position 191, causing the glutamic acid (E) at amino acid position 64 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0080	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.81
MVP		0.50
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.76

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: rs1003547108; hg19: chr15-44581418;