rs587777504

Variant names:

• chr4-129039039-A-G
• rs587777504
• NM_144643.4:c.290+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144643.4(SCLT1):​c.290+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000732 in 1,366,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SCLT1 NM_144643.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9888
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 4.39
• Publications: 4 publications found

Genes affected

SCLT1 (HGNC:26406): (sodium channel and clathrin linker 1) This gene encodes an adaptor protein. Studies of a related gene in rat suggest that the encoded protein functions to link clathrin to the sodium channel protein type 10 subunit alpha protein. The encoded protein has also been identified as a component of distal appendages of centrioles that is necessary for ciliogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

SCLT1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• Bardet-Biedl syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• Senior-Loken syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.4, offset of 44, new splice context is: tagGTaact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-129039039-A-G is Pathogenic according to our data. Variant chr4-129039039-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 139612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144643.4. 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
	SCLT1	NM_144643.4	MANE Select	c.290+2T>C		splice_donor intron	N/A	NP_653244.2	Q96NL6-1
	SCLT1	NM_001410807.1		c.290+2T>C		splice_donor intron	N/A	NP_001397736.1	A0A494C0G8
	SCLT1	NM_001300898.2		c.290+2T>C		splice_donor intron	N/A	NP_001287827.1	D6RBA6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCLT1	ENST00000281142.10	TSL:2 MANE Select	c.290+2T>C		splice_donor intron	N/A	ENSP00000281142.5	Q96NL6-1
	SCLT1	ENST00000503215.5	TSL:1	c.221+2T>C		splice_donor intron	N/A	ENSP00000424029.1	D6RBP0
	SCLT1	ENST00000439369.6	TSL:1	c.290+2T>C		splice_donor intron	N/A	ENSP00000395292.2	Q96NL6-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1366152 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 685216

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

African (AFR) AF: 0.0000317 AC: 1 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 39120

South Asian (SAS) AF: 0.00 AC: 0 AN: 83926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1026096

Other (OTH) AF: 0.00 AC: 0 AN: 57098

⚠️ 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.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		4.4
GERP RS		4.8
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777504; hg19: chr4-129960194;