chr15-44380901-G-A

Position:

• chr15-44380901-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138423.4(GOLM2):​c.997G>A​(p.Glu333Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GOLM2 NM_138423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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]

GOLM2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1567947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GOLM2	NM_138423.4	c.997G>A	p.Glu333Lys	missense_variant	8/10	ENST00000299957.11	NP_612432.2
GOLM2	NM_177974.3	c.997G>A	p.Glu333Lys	missense_variant	8/9		NP_816929.1
GOLM2	NR_157849.2	n.2700G>A		non_coding_transcript_exon_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GOLM2	ENST00000299957.11	c.997G>A	p.Glu333Lys	missense_variant	8/10	1	NM_138423.4	ENSP00000299957.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246062 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The c.997G>A (p.E333K) alteration is located in exon 8 (coding exon 8) of the CASC4 gene. This alteration results from a G to A substitution at nucleotide position 997, causing the glutamic acid (E) at amino acid position 333 to be replaced by a lysine (K). 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	Benign	0.070
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.057
Sift	Uncertain	0.018	D;.;D
Sift4G	Benign	0.77	T;.;D
Polyphen		0.62	.;.;P
Vest4		0.25
MutPred		0.24		Gain of ubiquitination at E333 (P = 0.0109);.;Gain of ubiquitination at E333 (P = 0.0109);
MVP		0.28
MPC		0.98
ClinPred		0.81	D
GERP RS		3.3
gMVP		0.24

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: rs1426236462; hg19: chr15-44673099;