Genetic Variant SS18L1:p.Arg9Trp (chr20-62143845-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_198935.3(SS18L1):c.25C>T(p.Arg9Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,178,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

SS18L1
NM_198935.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

Publications

1 publications found

Variant links:

Genes affected

SS18L1 (HGNC:15592): (SS18L1 subunit of BAF chromatin remodeling complex) This gene encodes a calcium-responsive transactivator which is an essential subunit of a neuron-specific chromatin-remodeling complex. The structure of this gene is similar to that of the SS18 gene. Mutations in this gene are involved in amyotrophic lateral sclerosis (ALS). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

SS18L1 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

SS18L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SS18L1	NM_198935.3 link	c.25C>T	p.Arg9Trp	missense_variant	Exon 1 of 11	ENST00000331758.8	NP_945173.1	O75177-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SS18L1	ENST00000331758.8 link	c.25C>T	p.Arg9Trp	missense_variant	Exon 1 of 11	1	NM_198935.3	ENSP00000333012.3	O75177-1
SS18L1	ENST00000450482.5 link	c.-346C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5	5		ENSP00000398634.1	Q9BR54
SS18L1	ENST00000450482.5 link	c.-346C>T		5_prime_UTR_variant	Exon 1 of 5	5		ENSP00000398634.1	Q9BR54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000170

AC:

AN:

1178952

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

585498

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23394

American (AMR)

AF:

0.00

AC:

AN:

29174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16486

East Asian (EAS)

AF:

0.00

AC:

AN:

18342

South Asian (SAS)

AF:

0.00

AC:

AN:

66888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4260

European-Non Finnish (NFE)

AF:

0.00000212

AC:

AN:

941786

Other (OTH)

AF:

0.00

AC:

AN:

42508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.25C>T (p.R9W) alteration is located in exon 1 (coding exon 1) of the SS18L1 gene. This alteration results from a C to T substitution at nucleotide position 25, causing the arginine (R) at amino acid position 9 to be replaced by a tryptophan (W). 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

Pathogenic

0.97

BayesDel_addAF

Benign

0.0035

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

0.041

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

PhyloP100

2.7

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.26

Sift

Benign

0.036

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.67

MutPred

0.42

Loss of disorder (P = 0.0011);

MVP

0.51

MPC

1.0

ClinPred

0.94

GERP RS

3.0

PromoterAI

-0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.49

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over