chr15-100569122-CAA-C

Variant names:

• chr15-100569122-CAA-C
• rs56225071
• NM_001040616.3:c.*114_*115delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001040616.3(LINS1):​c.*114_*115delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00881 in 468,770 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.0233) population. However there is too low homozygotes in high coverage region: (expected more than 9, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.*114_*115delTT		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.*114_*115delTT		3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000560783.1	n.191-3859_191-3858delTT		intron_variant	Intron 1 of 3	5		ENSP00000474128.1
LINS1	ENST00000559169.1	n.*111_*112delTT		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000471 AC: 5 AN: 106092 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000108

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: 0.0000545

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0114 AC: 4124 AN: 362678 Hom.: 0 AF XY: 0.0113 AC XY: 2172 AN XY: 191544

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

African (AFR) AF: 0.00942 AC: 98 AN: 10398

American (AMR) AF: 0.0137 AC: 196 AN: 14272

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 157 AN: 10504

East Asian (EAS) AF: 0.0249 AC: 603 AN: 24206

South Asian (SAS) AF: 0.00908 AC: 331 AN: 36470

European-Finnish (FIN) AF: 0.0127 AC: 252 AN: 19878

Middle Eastern (MID) AF: 0.0143 AC: 21 AN: 1470

European-Non Finnish (NFE) AF: 0.00988 AC: 2227 AN: 225496

Other (OTH) AF: 0.0120 AC: 239 AN: 19984

⚠️ 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: 0.0000471 AC: 5 AN: 106092 Hom.: 0 Cov.: 0 AF XY: 0.0000617 AC XY: 3 AN XY: 48614

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

African (AFR) AF: 0.0000363 AC: 1 AN: 27544

American (AMR) AF: 0.000108 AC: 1 AN: 9288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2882

East Asian (EAS) AF: 0.00 AC: 0 AN: 2986

South Asian (SAS) AF: 0.00 AC: 0 AN: 2972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000545 AC: 3 AN: 55048

Other (OTH) AF: 0.00 AC: 0 AN: 1342

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

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: rs56225071; hg19: chr15-101109327;