rs11247226

Variant names:

• chr15-100580758-T-C
• rs11247226
• NM_001040616.3:c.85A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040616.3(LINS1):​c.85A>G​(p.Ile29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,608,252 control chromosomes in the GnomAD database, including 158,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11065 hom., cov: 32)
  • Exomes 𝑓: 0.44 (147425 hom.)
• Consequence: LINS1 NM_001040616.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.76
• Publications: 53 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.19182696E-4).
• BP6: Variant 15-100580758-T-C is Benign according to our data. Variant chr15-100580758-T-C is described in ClinVar as Benign. ClinVar VariationId is 587785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.85A>G	p.Ile29Val	missense_variant	Exon 2 of 7	ENST00000314742.13	NP_001035706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LINS1	ENST00000314742.13	c.85A>G	p.Ile29Val	missense_variant	Exon 2 of 7	5	NM_001040616.3	ENSP00000318423.8

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55183 AN: 151904 Hom.: 11064 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.374 AC: 93282 AN: 249322 AF XY: 0.388

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.443 AC: 645435 AN: 1456230 Hom.: 147425 Cov.: 37 AF XY: 0.444 AC XY: 320851 AN XY: 723264

African (AFR) AF: 0.217 AC: 7245 AN: 33330

American (AMR) AF: 0.199 AC: 8825 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 9827 AN: 26040

East Asian (EAS) AF: 0.260 AC: 10275 AN: 39558

South Asian (SAS) AF: 0.387 AC: 33306 AN: 86064

European-Finnish (FIN) AF: 0.412 AC: 21945 AN: 53300

Middle Eastern (MID) AF: 0.392 AC: 2249 AN: 5742

European-Non Finnish (NFE) AF: 0.475 AC: 526565 AN: 1107658

Other (OTH) AF: 0.419 AC: 25198 AN: 60118

GnomAD4 genome AF: 0.363 AC: 55200 AN: 152022 Hom.: 11065 Cov.: 32 AF XY: 0.360 AC XY: 26738 AN XY: 74320

African (AFR) AF: 0.221 AC: 9170 AN: 41482

American (AMR) AF: 0.270 AC: 4110 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1400 AN: 3468

East Asian (EAS) AF: 0.242 AC: 1255 AN: 5176

South Asian (SAS) AF: 0.370 AC: 1782 AN: 4816

European-Finnish (FIN) AF: 0.407 AC: 4300 AN: 10570

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31888 AN: 67954

Other (OTH) AF: 0.373 AC: 783 AN: 2102

Alfa AF: 0.422 Hom.: 55241

Bravo AF: 0.344

TwinsUK AF: 0.472 AC: 1751

ALSPAC AF: 0.471 AC: 1816

ESP6500AA AF: 0.229 AC: 1008

ESP6500EA AF: 0.470 AC: 4039

ExAC AF: 0.380 AC: 46131

Asia WGS AF: 0.287 AC: 1000 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Mar 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0020
DANN	Benign	0.58
DEOGEN2	Benign	0.0021	T;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.53	T;T;T;T;T;T
MetaRNN	Benign	0.00012	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.060	N;N;.;.;.;.
PhyloP100		-2.8
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.020	N;N;N;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.72	T;T;T;T;T;T
Sift4G	Benign	0.95	T;T;.;.;T;T
Polyphen		0.0010	B;B;.;.;.;.
Vest4		0.074
MPC		0.020
ClinPred		0.0078	T
GERP RS		-4.7
La Branchor		0.54
Varity_R		0.014
gMVP		0.061
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11247226; hg19: chr15-101120963; COSMIC: COSV59079075; COSMIC: COSV59079075;