Genetic Variant LINS1:c.*113_*115dupTTT (chr15-100569122-C-CAAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001040616.3(LINS1):c.*113_*115dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.037 ( 174 hom., cov: 0)

Exomes 𝑓: 0.065 ( 13 hom. )

Consequence

LINS1
NM_001040616.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.597

Publications

0 publications found

Variant links:

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

LINS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0373 (3947/105778) while in subpopulation NFE AF = 0.0464 (2541/54818). AF 95% confidence interval is 0.0449. There are 174 homozygotes in GnomAd4. There are 1717 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 174 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINS1	NM_001040616.3 link	c.113_115dupTTT		3_prime_UTR_variant	Exon 7 of 7	ENST00000314742.13	NP_001035706.2	Q8NG48-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LINS1	ENST00000314742.13 link	c.113_115dupTTT	3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8	Q8NG48-1
LINS1	ENST00000560783.1 link	n.191-3860_191-3858dupTTT	intron_variant	Intron 1 of 3	5		ENSP00000474128.1	S4R3B7
LINS1	ENST00000559169.1 link	n.110_112dupTTT	downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0373

AC:

3949

AN:

105792

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0241

Gnomad AMI

AF:

0.0539

Gnomad AMR

AF:

0.0255

Gnomad ASJ

AF:

0.0728

Gnomad EAS

AF:

0.00168

Gnomad SAS

AF:

0.0344

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.105

Gnomad NFE

AF:

0.0464

Gnomad OTH

AF:

0.0455

GnomAD4 exome

AF:

0.0648

AC:

23508

AN:

362600

Hom.:

Cov.:

AF XY:

0.0655

AC XY:

12542

AN XY:

191454

show subpopulations

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

African (AFR)

AF:

0.0550

AC:

568

AN:

10330

American (AMR)

AF:

0.0394

AC:

566

AN:

14382

Ashkenazi Jewish (ASJ)

AF:

0.0677

AC:

709

AN:

10470

East Asian (EAS)

AF:

0.0236

AC:

593

AN:

25076

South Asian (SAS)

AF:

0.0632

AC:

2299

AN:

36404

European-Finnish (FIN)

AF:

0.0586

AC:

1167

AN:

19918

Middle Eastern (MID)

AF:

0.0739

AC:

109

AN:

1474

European-Non Finnish (NFE)

AF:

0.0724

AC:

16250

AN:

224596

Other (OTH)

AF:

0.0625

AC:

1247

AN:

19950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

1605

3210

4816

6421

8026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0373

AC:

3947

AN:

105778

Hom.:

174

Cov.:

AF XY:

0.0354

AC XY:

1717

AN XY:

48496

show subpopulations

African (AFR)

AF:

0.0241

AC:

663

AN:

27524

American (AMR)

AF:

0.0255

AC:

237

AN:

9292

Ashkenazi Jewish (ASJ)

AF:

0.0728

AC:

209

AN:

2870

East Asian (EAS)

AF:

0.00169

AC:

AN:

2966

South Asian (SAS)

AF:

0.0347

AC:

102

AN:

2942

European-Finnish (FIN)

AF:

0.0215

AC:

AN:

3022

Middle Eastern (MID)

AF:

0.109

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.0464

AC:

2541

AN:

54818

Other (OTH)

AF:

0.0451

AC:

AN:

1354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

157

313

470

626

783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.60

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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chr15-100569122-C-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over