rs144513217

Variant names:

• chr15-100570033-A-G
• rs144513217
• NM_001040616.3:c.1479T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040616.3(LINS1):​c.1479T>C​(p.Cys493Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,557,222 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: LINS1 NM_001040616.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0820
• Publications: 0 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-100570033-A-G is Benign according to our data. Variant chr15-100570033-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 435759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.082 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000321 (451/1404860) while in subpopulation MID AF = 0.00344 (19/5518). AF 95% confidence interval is 0.00225. There are 3 homozygotes in GnomAdExome4. There are 229 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.1479T>C	p.Cys493Cys	synonymous	Exon 7 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352508.2		c.1326T>C	p.Cys442Cys	synonymous	Exon 7 of 7	NP_001339437.1
	LINS1	NM_001352507.2		c.732T>C	p.Cys244Cys	synonymous	Exon 8 of 8	NP_001339436.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINS1	ENST00000314742.13	TSL:5 MANE Select	c.1479T>C	p.Cys493Cys	synonymous	Exon 7 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000869609.1		c.1443T>C	p.Cys481Cys	synonymous	Exon 7 of 7	ENSP00000539668.1
	LINS1	ENST00000869606.1		c.1434T>C	p.Cys478Cys	synonymous	Exon 7 of 7	ENSP00000539665.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000358 AC: 74 AN: 206480 AF XY: 0.000420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000596

Gnomad OTH exome AF: 0.000801

GnomAD4 exome AF: 0.000321 AC: 451 AN: 1404860 Hom.: 3 Cov.: 31 AF XY: 0.000329 AC XY: 229 AN XY: 695744

African (AFR) AF: 0.0000953 AC: 3 AN: 31494

American (AMR) AF: 0.000594 AC: 22 AN: 37026

Ashkenazi Jewish (ASJ) AF: 0.0000419 AC: 1 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.000216 AC: 17 AN: 78602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40200

Middle Eastern (MID) AF: 0.00344 AC: 19 AN: 5518

European-Non Finnish (NFE) AF: 0.000315 AC: 344 AN: 1090508

Other (OTH) AF: 0.000772 AC: 45 AN: 58272

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.000362 AC XY: 27 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.000914 AC: 14 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.000446

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.4
DANN	Benign	0.66
PhyloP100		0.082
Mutation Taster		=100/0	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: rs144513217; hg19: chr15-101110238;