rs141782332

Variant names:

• chr15-100580791-C-T
• rs141782332
• NM_001040616.3:c.52G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001040616.3(LINS1):​c.52G>A​(p.Gly18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,610,368 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: LINS1 NM_001040616.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.50
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067200065).
• BP6: Variant 15-100580791-C-T is Benign according to our data. Variant chr15-100580791-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520599.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.002 (305/152252) while in subpopulation AFR AF = 0.00693 (288/41556). AF 95% confidence interval is 0.00627. There are 1 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.52G>A	p.Gly18Arg	missense	Exon 2 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352508.2		c.52G>A	p.Gly18Arg	missense	Exon 2 of 7	NP_001339437.1
	LINS1	NM_001352507.2		c.-858G>A		5_prime_UTR	Exon 2 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.52G>A	p.Gly18Arg	missense	Exon 2 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000561308.5	TSL:1	c.52G>A	p.Gly18Arg	missense	Exon 2 of 5	ENSP00000454200.1	Q8NG48-2
	LINS1	ENST00000869609.1		c.52G>A	p.Gly18Arg	missense	Exon 2 of 7	ENSP00000539668.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152134 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000558 AC: 139 AN: 248902 AF XY: 0.000342

Gnomad AFR exome AF: 0.00686

Gnomad AMR exome AF: 0.000676

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000215 AC: 314 AN: 1458116 Hom.: 1 Cov.: 32 AF XY: 0.000168 AC XY: 122 AN XY: 724764

African (AFR) AF: 0.00674 AC: 225 AN: 33372

American (AMR) AF: 0.000767 AC: 34 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5740

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109700

Other (OTH) AF: 0.000747 AC: 45 AN: 60202

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152252 Hom.: 1 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74450

African (AFR) AF: 0.00693 AC: 288 AN: 41556

American (AMR) AF: 0.000785 AC: 12 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000712 Hom.: 2

Bravo AF: 0.00232

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000692 AC: 84

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	LINS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.49		Loss of sheet (P = 0.0063)
MVP		0.25
MPC		0.18
ClinPred		0.027	T
GERP RS		3.8
Varity_R		0.077
gMVP		0.52
Mutation Taster		=89/11	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: rs141782332; hg19: chr15-101120996;