15-100569122-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001040616.3(LINS1):​c.*112_*115dupTTTT 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 0.00024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0072 (2 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040616.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINS1	NM_001040616.3	MANE Select	c.*112_*115dupTTTT		3_prime_UTR	Exon 7 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352508.2		c.*112_*115dupTTTT		3_prime_UTR	Exon 7 of 7	NP_001339437.1
	LINS1	NM_001352507.2		c.*112_*115dupTTTT		3_prime_UTR	Exon 8 of 8	NP_001339436.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINS1	ENST00000314742.13	TSL:5 MANE Select	c.*112_*115dupTTTT		3_prime_UTR	Exon 7 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000869606.1		c.*112_*115dupTTTT		3_prime_UTR	Exon 7 of 7	ENSP00000539665.1
	LINS1	ENST00000869607.1		c.*112_*115dupTTTT		3_prime_UTR	Exon 7 of 7	ENSP00000539666.1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 25 AN: 106068 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000108

Gnomad ASJ AF: 0.000347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000336

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000273

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00723 AC: 2665 AN: 368472 Hom.: 2 Cov.: 5 AF XY: 0.00710 AC XY: 1380 AN XY: 194494

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

African (AFR) AF: 0.00750 AC: 79 AN: 10532

American (AMR) AF: 0.00416 AC: 61 AN: 14646

Ashkenazi Jewish (ASJ) AF: 0.00881 AC: 94 AN: 10664

East Asian (EAS) AF: 0.00162 AC: 41 AN: 25340

South Asian (SAS) AF: 0.00751 AC: 279 AN: 37126

European-Finnish (FIN) AF: 0.00590 AC: 119 AN: 20176

Middle Eastern (MID) AF: 0.00533 AC: 8 AN: 1500

European-Non Finnish (NFE) AF: 0.00806 AC: 1840 AN: 228216

Other (OTH) AF: 0.00710 AC: 144 AN: 20272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000236 AC: 25 AN: 106054 Hom.: 0 Cov.: 0 AF XY: 0.000267 AC XY: 13 AN XY: 48606

African (AFR) AF: 0.000254 AC: 7 AN: 27562

American (AMR) AF: 0.000108 AC: 1 AN: 9298

Ashkenazi Jewish (ASJ) AF: 0.000347 AC: 1 AN: 2882

East Asian (EAS) AF: 0.00 AC: 0 AN: 2970

South Asian (SAS) AF: 0.000339 AC: 1 AN: 2948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3028

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

European-Non Finnish (NFE) AF: 0.000273 AC: 15 AN: 55018

Other (OTH) AF: 0.00 AC: 0 AN: 1356

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56225071; hg19: chr15-101109327;