15-44379749-C-G

Variant names:

• chr15-44379749-C-G
• rs142590512
• NM_138423.4:c.862C>G

Variant summary

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

The NM_138423.4(GOLM2):​c.862C>G​(p.Leu288Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,451,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GOLM2 NM_138423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.220
• Publications: 0 publications found

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

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=0.09389064).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138423.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GOLM2	NM_138423.4	MANE Select	c.862C>G	p.Leu288Val	missense	Exon 7 of 10	NP_612432.2
	GOLM2	NM_177974.3		c.862C>G	p.Leu288Val	missense	Exon 7 of 9	NP_816929.1	Q6P4E1-2
	GOLM2	NR_157849.2		n.2565C>G		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GOLM2	ENST00000299957.11	TSL:1 MANE Select	c.862C>G	p.Leu288Val	missense	Exon 7 of 10	ENSP00000299957.6	Q6P4E1-4
	GOLM2	ENST00000345795.6	TSL:1	c.862C>G	p.Leu288Val	missense	Exon 7 of 9	ENSP00000335063.4	Q6P4E1-2
	GOLM2	ENST00000915850.1		c.847C>G	p.Leu283Val	missense	Exon 7 of 10	ENSP00000585909.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1451220 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721872

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33210

American (AMR) AF: 0.00 AC: 0 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 38948

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1104522

Other (OTH) AF: 0.00 AC: 0 AN: 59768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000233207), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.97
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.22
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.024
Sift	Benign	0.41	T
Sift4G	Benign	0.45	T
Polyphen		0.012	B
Vest4		0.20
MVP		0.17
MPC		0.44
ClinPred		0.041	T
GERP RS		0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.18
Mutation Taster		=94/6	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: rs142590512; hg19: chr15-44671947;