chr20-62159959-G-C

Variant names:

• chr20-62159959-G-C
• rs1471031064
• NM_198935.3:c.229G>C

Variant summary

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

The NM_198935.3(SS18L1):​c.229G>C​(p.Ala77Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A77T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: SS18L1 NM_198935.3 missense, splice_region
• Scores: Splicing: ADA: 0.9470
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.37
• Publications: 2 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37754208).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SS18L1	NM_198935.3	MANE Select	c.229G>C	p.Ala77Pro	missense splice_region	Exon 3 of 11	NP_945173.1	O75177-1
	SS18L1	NM_001301778.2		c.-85G>C		splice_region	Exon 4 of 12	NP_001288707.1	O75177-4
	SS18L1	NM_001301778.2		c.-85G>C		5_prime_UTR	Exon 4 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.229G>C	p.Ala77Pro	missense splice_region	Exon 3 of 11	ENSP00000333012.3	O75177-1
	SS18L1	ENST00000450482.5	TSL:5	c.238G>C	p.Ala80Pro	missense splice_region	Exon 4 of 5	ENSP00000398634.1	Q9BR54

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74202

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.28
Sift	Benign	0.049	D
Sift4G	Uncertain	0.052	T
Polyphen		0.82	P
Vest4		0.75
MutPred		0.24		Gain of glycosylation at A77 (P = 0.0018)
MVP		0.31
MPC		1.3
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.40
gMVP		0.86
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.75
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: rs1471031064; hg19: chr20-60735015;