12-13084953-C-A

Variant names:

• chr12-13084953-C-A
• rs746633593
• NM_001080555.4:c.1037G>T

Variant summary

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

The NM_001080555.4(GSG1):​c.1037G>T​(p.Ser346Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GSG1 NM_001080555.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583

Genes affected

GSG1 (HGNC:19716): (germ cell associated 1) Predicted to enable RNA polymerase binding activity. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FAM234B (HGNC:29288): (family with sequence similarity 234 member B) Predicted to be located in Golgi apparatus and cytoskeleton. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.0853214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSG1	NM_001080555.4	c.1037G>T	p.Ser346Ile	missense_variant	Exon 7 of 7	ENST00000651961.1	NP_001074024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSG1	ENST00000651961.1	c.1037G>T	p.Ser346Ile	missense_variant	Exon 7 of 7		NM_001080555.4	ENSP00000498528.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000126 AC: 2 AN: 158506 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000807

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399480 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1037G>T (p.S346I) alteration is located in exon 7 (coding exon 7) of the GSG1 gene. This alteration results from a G to T substitution at nucleotide position 1037, causing the serine (S) at amino acid position 346 to be replaced by an isoleucine (I). 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
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.94
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.57	T;T;T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.065	T;T;T;T
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.0020, 0.034	.;B;B;B
Vest4		0.10
MVP		0.16
MPC		0.15
ClinPred		0.031	T
GERP RS		1.4
gMVP		0.40

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: rs746633593; hg19: chr12-13237887;