15-100569122-CAAAA-C

Variant names:

• chr15-100569122-CAAAA-C
• rs56225071
• NM_001040616.3:c.*112_*115delTTTT

Variant summary

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

The NM_001040616.3(LINS1):​c.*112_*115delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 476,348 control chromosomes in the GnomAD database, including 52 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (51 hom., cov: 0)
  • Exomes 𝑓: 0.0029 (1 hom.)
• Consequence: LINS1 NM_001040616.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.973
• 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-CAAAA-C is Benign according to our data. Variant chr15-100569122-CAAAA-C is described in ClinVar as [Benign]. Clinvar id is 1236361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.*112_*115delTTTT		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.*112_*115delTTTT		3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000560783.1	n.191-3861_191-3858delTTTT		intron_variant	Intron 1 of 3	5		ENSP00000474128.1
LINS1	ENST00000559169.1	n.*109_*112delTTTT		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 1961 AN: 106108 Hom.: 51 Cov.: 0

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00743

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000673

Gnomad FIN AF: 0.000330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.0171

GnomAD4 exome AF: 0.00287 AC: 1061 AN: 370254 Hom.: 1 AF XY: 0.00232 AC XY: 454 AN XY: 195474

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

African (AFR) AF: 0.0586 AC: 618 AN: 10538

American (AMR) AF: 0.00512 AC: 75 AN: 14662

Ashkenazi Jewish (ASJ) AF: 0.00131 AC: 14 AN: 10718

East Asian (EAS) AF: 0.00111 AC: 28 AN: 25222

South Asian (SAS) AF: 0.000669 AC: 25 AN: 37396

European-Finnish (FIN) AF: 0.000989 AC: 20 AN: 20224

Middle Eastern (MID) AF: 0.00133 AC: 2 AN: 1508

European-Non Finnish (NFE) AF: 0.000753 AC: 173 AN: 229624

Other (OTH) AF: 0.00521 AC: 106 AN: 20362

⚠️ 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: 0.0185 AC: 1958 AN: 106094 Hom.: 51 Cov.: 0 AF XY: 0.0192 AC XY: 932 AN XY: 48628

African (AFR) AF: 0.0672 AC: 1854 AN: 27570

American (AMR) AF: 0.00742 AC: 69 AN: 9300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2972

South Asian (SAS) AF: 0.000678 AC: 2 AN: 2948

European-Finnish (FIN) AF: 0.000330 AC: 1 AN: 3028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.000163 AC: 9 AN: 55046

Other (OTH) AF: 0.0170 AC: 23 AN: 1356

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 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
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;