15-100569122-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAA

Variant names:

• chr15-100569122-C-CAAA
• rs56225071
• NM_001040616.3:c.*113_*115dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.597
• 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 -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	c.*113_*115dupTTT		3_prime_UTR_variant	Exon 7 of 7	ENST00000314742.13	NP_001035706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LINS1	ENST00000314742.13	c.*113_*115dupTTT		3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000560783.1	n.191-3860_191-3858dupTTT		intron_variant	Intron 1 of 3	5		ENSP00000474128.1
LINS1	ENST00000559169.1	n.*110_*112dupTTT		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 3949 AN: 105792 Hom.: 174 Cov.: 0

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.: 13 Cov.: 5 AF XY: 0.0655 AC XY: 12542 AN XY: 191454

⚠️ 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.

GnomAD4 genome AF: 0.0373 AC: 3947 AN: 105778 Hom.: 174 Cov.: 0 AF XY: 0.0354 AC XY: 1717 AN XY: 48496

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: 5 AN: 2966

South Asian (SAS) AF: 0.0347 AC: 102 AN: 2942

European-Finnish (FIN) AF: 0.0215 AC: 65 AN: 3022

Middle Eastern (MID) AF: 0.109 AC: 21 AN: 192

European-Non Finnish (NFE) AF: 0.0464 AC: 2541 AN: 54818

Other (OTH) AF: 0.0451 AC: 61 AN: 1354

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs56225071; hg19: chr15-101109327;