18-26052672-T-C

Position:

• chr18-26052672-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001007559.3(SS18):​c.559A>G​(p.Met187Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SS18 NM_001007559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

SS18 (HGNC:11340): (SS18 subunit of BAF chromatin remodeling complex) Enables nuclear receptor coactivator activity. Involved in positive regulation of transcription by RNA polymerase II. Part of SWI/SNF complex. Implicated in synovial sarcoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2827428).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SS18	NM_001007559.3	c.559A>G	p.Met187Val	missense_variant	5/11	ENST00000415083.7	NP_001007560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SS18	ENST00000415083.7	c.559A>G	p.Met187Val	missense_variant	5/11	1	NM_001007559.3	ENSP00000414516	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

May 02, 2024

The c.559A>G (p.M187V) alteration is located in exon 5 (coding exon 5) of the SS18 gene. This alteration results from a A to G substitution at nucleotide position 559, causing the methionine (M) at amino acid position 187 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	0.059
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.59	.;N;N
REVEL	Benign	0.097
Sift	Benign	0.12	.;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.23	B;.;.
Vest4		0.51
MutPred		0.26		Gain of catalytic residue at M187 (P = 0.0942);.;Gain of catalytic residue at M187 (P = 0.0942);
MVP		0.14
MPC		0.21
ClinPred		0.62	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2053942474; hg19: chr18-23632636;