Genetic Variant SS18L1:p.Met1? (chr20-62161451-A-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The ENST00000370848.8(SS18L1):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000822 in 1,460,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SS18L1
ENST00000370848.8 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.70

Publications

0 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 -3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 50 codons. Genomic position: 62162769. Lost 0.157 part of the original CDS.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SS18L1	NM_198935.3 link	c.247A>G	p.Met83Val	missense_variant	Exon 4 of 11	ENST00000331758.8	NP_945173.1	O75177-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SS18L1	ENST00000370848.8 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	1		ENSP00000359885.5	O75177-3
SS18L1	ENST00000331758.8 link	c.247A>G	p.Met83Val	missense_variant	Exon 4 of 11	1	NM_198935.3	ENSP00000333012.3	O75177-1
SS18L1	ENST00000450482.5 link	c.256A>G	p.Met86Val	missense_variant	Exon 5 of 5	5		ENSP00000398634.1	Q9BR54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249156

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460654

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.40

.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

T;T;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M;.

PhyloP100

5.7

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.016

D;D;D

Sift4G

Uncertain

0.037

D;T;D

Polyphen

0.18

.;B;.

Vest4

0.52, 0.76

MutPred

0.21

.;Loss of sheet (P = 0.1907);.;

MVP

0.26

MPC

0.43

ClinPred

0.23

GERP RS

3.1

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.55

Mutation Taster

=78/22

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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20-62161451-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over