Genetic Variant SS18L1:p.Ile123Met (chr20-62161573-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198935.3(SS18L1):c.369T>G(p.Ile123Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

SS18L1
NM_198935.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.354

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03998977).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198935.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SS18L1	NM_198935.3	MANE Select	c.369T>G	p.Ile123Met	missense	Exon 4 of 11	NP_945173.1
SS18L1	NM_001301778.2		c.-25T>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 12	NP_001288707.1
SS18L1	NR_125980.3		n.800T>G		non_coding_transcript_exon	Exon 5 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SS18L1	ENST00000331758.8	TSL:1 MANE Select	c.369T>G	p.Ile123Met	missense	Exon 4 of 11	ENSP00000333012.3
SS18L1	ENST00000370848.8	TSL:1	c.123T>G	p.Ile41Met	missense	Exon 1 of 9	ENSP00000359885.5
SS18L1	ENST00000450482.5	TSL:5	c.378T>G	p.Ile126Met	missense	Exon 5 of 5	ENSP00000398634.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 01, 2013

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.2

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.026

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.63

M_CAP

Benign

0.060

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.57

PhyloP100

-0.35

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.65

REVEL

Benign

0.098

Sift

Benign

0.52

Sift4G

Benign

0.71

Polyphen

0.21

Vest4

0.35

MutPred

0.20

Loss of catalytic residue at I123 (P = 0.0444)

MVP

0.14

MPC

0.96

ClinPred

0.21

GERP RS

-1.1

PromoterAI

-0.093

Neutral

(source)

Varity_R

0.13

gMVP

0.26

Mutation Taster

=6/94

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over