rs587777226

Variant names:

• chr15-100573649-ACCTTT-A
• rs587777226
• ENST00000561308.5:c.1219_1223delAAAGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001040616.3(LINS1):​c.1219_1222+1delAAAGG​(p.Lys407fs) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LINS1 NM_001040616.3 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.83
• Publications: 2 publications found

Genes affected

LINS1 (HGNC:30922): (lines homolog 1) The Drosophila segment polarity gene lin encodes a protein, lines, which plays important roles in development of the epidermis and hindgut. This gene encodes a protein containing a lines-like domain. This gene is located on chromosome 15 and clustered with the gene encoding ankyrin repeat and SOCS box-containing protein 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

LINS1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 27

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-100573649-ACCTTT-A is Pathogenic according to our data. Variant chr15-100573649-ACCTTT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 120183.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040616.3. 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
	LINS1	NM_001040616.3	MANE Select	c.1219_1222+1delAAAGG	p.Lys407fs	frameshift splice_donor splice_region intron	Exon 5 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352508.2		c.1174_1177+1delAAAGG	p.Lys392fs	frameshift splice_donor splice_region intron	Exon 5 of 7	NP_001339437.1
	LINS1	NM_001352507.2		c.472_475+1delAAAGG	p.Lys158fs	frameshift splice_donor splice_region intron	Exon 6 of 8	NP_001339436.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINS1	ENST00000561308.5	TSL:1	c.1219_1223delAAAGG	p.Lys407fs	frameshift	Exon 5 of 5	ENSP00000454200.1	Q8NG48-2
	LINS1	ENST00000314742.13	TSL:5 MANE Select	c.1219_1222+1delAAAGG	p.Lys407fs	frameshift splice_donor splice_region intron	Exon 5 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000560133.5	TSL:2	c.862_866delAAAGG	p.Lys288fs	frameshift	Exon 5 of 5	ENSP00000454929.1	H3BNM9

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability (1)
1	-	-	Intellectual disability, autosomal recessive 27 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587777226; hg19: chr15-101113854;