rs751255404

Variant names:

• chr20-62161451-A-C
• rs751255404
• NM_198935.3:c.247A>C

Your query was ambiguous. Multiple possible variants found:

• chr20-62161451-A-C
• chr20-62161451-A-G
• chr20-62161451-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198935.3(SS18L1):​c.247A>C​(p.Met83Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M83K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SS18L1 NM_198935.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31241775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SS18L1	NM_198935.3	c.247A>C	p.Met83Leu	missense_variant	Exon 4 of 11	ENST00000331758.8	NP_945173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SS18L1	ENST00000331758.8	c.247A>C	p.Met83Leu	missense_variant	Exon 4 of 11	1	NM_198935.3	ENSP00000333012.3
SS18L1	ENST00000370848.8	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 9	1		ENSP00000359885.5
SS18L1	ENST00000450482.5	c.256A>C	p.Met86Leu	missense_variant	Exon 5 of 5	5		ENSP00000398634.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460654 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726624

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.21	.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.035	D;T;T
Polyphen		0.18	.;B;.
Vest4		0.29, 0.50
MutPred		0.19		.;Gain of sheet (P = 0.1945);.;
MVP		0.20
MPC		0.36
ClinPred		0.88	D
GERP RS		3.1
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.41
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs751255404; hg19: chr20-60736507;