15-100569122-C-CAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001040616.3(LINS1):​c.*114_*115dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (7309 hom., cov: 0)
  • Exomes 𝑓: 0.24 (157 hom.)
• Consequence: LINS1 NM_001040616.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 15-100569122-C-CAA is Benign according to our data. Variant chr15-100569122-C-CAA is described in ClinVar as [Benign]. Clinvar id is 1281296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.358 AC: 37809 AN: 105592 Hom.: 7314 Cov.: 0

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.319

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.240 AC: 86373 AN: 360468 Hom.: 157 Cov.: 5 AF XY: 0.240 AC XY: 45757 AN XY: 190336

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

African (AFR) AF: 0.219 AC: 2217 AN: 10138

American (AMR) AF: 0.173 AC: 2458 AN: 14202

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 2076 AN: 10358

East Asian (EAS) AF: 0.143 AC: 3490 AN: 24458

South Asian (SAS) AF: 0.235 AC: 8496 AN: 36198

European-Finnish (FIN) AF: 0.231 AC: 4577 AN: 19832

Middle Eastern (MID) AF: 0.225 AC: 330 AN: 1468

European-Non Finnish (NFE) AF: 0.260 AC: 58142 AN: 223992

Other (OTH) AF: 0.231 AC: 4587 AN: 19822

⚠️ 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: 0.358 AC: 37794 AN: 105578 Hom.: 7309 Cov.: 0 AF XY: 0.354 AC XY: 17124 AN XY: 48366

African (AFR) AF: 0.343 AC: 9417 AN: 27438

American (AMR) AF: 0.232 AC: 2145 AN: 9254

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 926 AN: 2864

East Asian (EAS) AF: 0.297 AC: 879 AN: 2956

South Asian (SAS) AF: 0.310 AC: 908 AN: 2932

European-Finnish (FIN) AF: 0.304 AC: 918 AN: 3016

Middle Eastern (MID) AF: 0.302 AC: 58 AN: 192

European-Non Finnish (NFE) AF: 0.398 AC: 21799 AN: 54772

Other (OTH) AF: 0.331 AC: 448 AN: 1354

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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;