16-27791449-G-A

Variant names:

• chr16-27791449-G-A
• rs199902586
• NM_001109763.2:c.917C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001109763.2(GSG1L):​c.917C>T​(p.Ala306Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,500,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GSG1L NM_001109763.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.255

Genes affected

GSG1L (HGNC:28283): (GSG1 like) Predicted to be involved in regulation of AMPA receptor activity. Predicted to be located in postsynaptic density. Predicted to be active in Schaffer collateral - CA1 synapse; glutamatergic synapse; and plasma membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017878681).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSG1L	NM_001109763.2	c.917C>T	p.Ala306Val	missense_variant	Exon 7 of 7	ENST00000447459.7	NP_001103233.1
GSG1L	NM_001323900.2	c.971C>T	p.Ala324Val	missense_variant	Exon 8 of 8		NP_001310829.1
GSG1L	NM_001323901.2	c.764C>T	p.Ala255Val	missense_variant	Exon 6 of 6		NP_001310830.1
GSG1L	NM_144675.3	c.452C>T	p.Ala151Val	missense_variant	Exon 6 of 6		NP_653276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSG1L	ENST00000447459.7	c.917C>T	p.Ala306Val	missense_variant	Exon 7 of 7	2	NM_001109763.2	ENSP00000394954.2
GSG1L	ENST00000395724.7	c.764C>T	p.Ala255Val	missense_variant	Exon 6 of 6	1		ENSP00000379074.3
GSG1L	ENST00000569166.1	c.506C>T	p.Ala169Val	missense_variant	Exon 6 of 6	1		ENSP00000454880.1
GSG1L	ENST00000380897.7	c.452C>T	p.Ala151Val	missense_variant	Exon 6 of 6	1		ENSP00000370282.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000443 AC: 8 AN: 180642 Hom.: 0 AF XY: 0.0000410 AC XY: 4 AN XY: 97512

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.0000880

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: 0.0000470

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000208 AC: 28 AN: 1348748 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 12 AN XY: 665094

Gnomad4 AFR exome AF: 0.000170

Gnomad4 AMR exome AF: 0.0000303

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000294

Gnomad4 SAS exome AF: 0.0000143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000364

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.917C>T (p.A306V) alteration is located in exon 7 (coding exon 7) of the GSG1L gene. This alteration results from a C to T substitution at nucleotide position 917, causing the alanine (A) at amino acid position 306 to be replaced by a valine (V). 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	0.085
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.0022	T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.95	N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.084	B;B;.;B
Vest4		0.050
MVP		0.44
MPC		0.45
ClinPred		0.017	T
GERP RS		-4.0
Varity_R		0.026
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199902586; hg19: chr16-27802770; COSMIC: COSV101093402;