15-100569049-A-G

Variant names:

• chr15-100569049-A-G
• rs3751551
• NM_001040616.3:c.*189T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040616.3(LINS1):​c.*189T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 146,660 control chromosomes in the GnomAD database, including 11,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11334 hom., cov: 24)
  • Exomes 𝑓: 0.39 (26080 hom.)
  • Failed GnomAD Quality Control
• Consequence: LINS1 NM_001040616.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.545
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 15-100569049-A-G is Benign according to our data. Variant chr15-100569049-A-G is described in ClinVar as [Benign]. Clinvar id is 1267299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.*189T>C		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.*189T>C		3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000560783.1	n.191-3784T>C		intron_variant	Intron 1 of 3	5		ENSP00000474128.1
LINS1	ENST00000559169.1	n.*186T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.383 AC: 56111 AN: 146572 Hom.: 11333 Cov.: 24

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.384

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.394 AC: 119563 AN: 303296 Hom.: 26080 Cov.: 2 AF XY: 0.393 AC XY: 63140 AN XY: 160546

African (AFR) AF: 0.258 AC: 2380 AN: 9212

American (AMR) AF: 0.221 AC: 2705 AN: 12234

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 3359 AN: 9628

East Asian (EAS) AF: 0.229 AC: 4754 AN: 20758

South Asian (SAS) AF: 0.368 AC: 12396 AN: 33668

European-Finnish (FIN) AF: 0.367 AC: 5575 AN: 15192

Middle Eastern (MID) AF: 0.363 AC: 499 AN: 1376

European-Non Finnish (NFE) AF: 0.443 AC: 81268 AN: 183656

Other (OTH) AF: 0.377 AC: 6627 AN: 17572

GnomAD4 genome AF: 0.383 AC: 56124 AN: 146660 Hom.: 11334 Cov.: 24 AF XY: 0.380 AC XY: 26970 AN XY: 71046

African (AFR) AF: 0.279 AC: 11022 AN: 39454

American (AMR) AF: 0.284 AC: 4090 AN: 14384

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1384 AN: 3438

East Asian (EAS) AF: 0.239 AC: 1182 AN: 4942

South Asian (SAS) AF: 0.370 AC: 1706 AN: 4608

European-Finnish (FIN) AF: 0.412 AC: 3896 AN: 9448

Middle Eastern (MID) AF: 0.427 AC: 123 AN: 288

European-Non Finnish (NFE) AF: 0.470 AC: 31558 AN: 67172

Other (OTH) AF: 0.383 AC: 779 AN: 2032

Alfa AF: 0.411 Hom.: 1648

Bravo AF: 0.361

Asia WGS AF: 0.277 AC: 964 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.9
DANN	Benign	0.046
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs3751551; hg19: chr15-101109254;