20-62143845-C-T

Variant names:

• chr20-62143845-C-T
• rs148870250
• NM_198935.3:c.25C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001301778.2(SS18L1):​c.-474C>T variant causes a 5 prime UTR premature start codon gain 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_001301778.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72
• Publications: 1 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: ClinGen, Genomics England PanelApp

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301778.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SS18L1	NM_198935.3	MANE Select	c.25C>T	p.Arg9Trp	missense	Exon 1 of 11	NP_945173.1	O75177-1
	SS18L1	NM_001301778.2		c.-474C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001288707.1	O75177-4
	SS18L1	NM_001301778.2		c.-474C>T		5_prime_UTR	Exon 1 of 12	NP_001288707.1	O75177-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SS18L1	ENST00000331758.8	TSL:1 MANE Select	c.25C>T	p.Arg9Trp	missense	Exon 1 of 11	ENSP00000333012.3	O75177-1
	SS18L1	ENST00000450482.5	TSL:5	c.-346C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000398634.1	Q9BR54
	SS18L1	ENST00000450482.5	TSL:5	c.-346C>T		5_prime_UTR	Exon 1 of 5	ENSP00000398634.1	Q9BR54

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000170 AC: 2 AN: 1178952 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 585498

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

African (AFR) AF: 0.00 AC: 0 AN: 23394

American (AMR) AF: 0.00 AC: 0 AN: 29174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16486

East Asian (EAS) AF: 0.00 AC: 0 AN: 18342

South Asian (SAS) AF: 0.00 AC: 0 AN: 66888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4260

European-Non Finnish (NFE) AF: 0.00000212 AC: 2 AN: 941786

Other (OTH) AF: 0.00 AC: 0 AN: 42508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	0.0035	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	0.041
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.26
Sift	Benign	0.036	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.42		Loss of disorder (P = 0.0011)
MVP		0.51
MPC		1.0
ClinPred		0.94	D
GERP RS		3.0
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.49
Mutation Taster		=52/48	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: rs148870250; hg19: chr20-60718901; COSMIC: COSV107389476; COSMIC: COSV107389476;