rs3751549

Variant names:

• chr15-100569022-A-G
• rs3751549
• NM_001040616.3:c.*216T>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.*216T>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 0.392 in 403,440 control chromosomes in the GnomAD database, including 33,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11460 hom., cov: 26)
  • Exomes 𝑓: 0.40 (22017 hom.)
• Consequence: LINS1 NM_001040616.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24
• Publications: 1 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=-1.0).
• BP6: Variant 15-100569022-A-G is Benign according to our data. Variant chr15-100569022-A-G is described in ClinVar as [Benign]. Clinvar id is 1283347.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.*216T>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.*216T>C		3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000560783.1	n.191-3757T>C		intron_variant	Intron 1 of 3	5		ENSP00000474128.1
LINS1	ENST00000559169.1	n.*213T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 56751 AN: 149908 Hom.: 11458 Cov.: 26

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.400 AC: 101438 AN: 253418 Hom.: 22017 Cov.: 0 AF XY: 0.398 AC XY: 53578 AN XY: 134590

African (AFR) AF: 0.263 AC: 2047 AN: 7790

American (AMR) AF: 0.225 AC: 2246 AN: 9978

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 2847 AN: 8030

East Asian (EAS) AF: 0.230 AC: 3836 AN: 16684

South Asian (SAS) AF: 0.371 AC: 11025 AN: 29700

European-Finnish (FIN) AF: 0.376 AC: 4245 AN: 11290

Middle Eastern (MID) AF: 0.368 AC: 400 AN: 1086

European-Non Finnish (NFE) AF: 0.449 AC: 69234 AN: 154320

Other (OTH) AF: 0.382 AC: 5558 AN: 14540

GnomAD4 genome AF: 0.378 AC: 56768 AN: 150022 Hom.: 11460 Cov.: 26 AF XY: 0.375 AC XY: 27365 AN XY: 73070

African (AFR) AF: 0.275 AC: 11217 AN: 40776

American (AMR) AF: 0.275 AC: 4144 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1390 AN: 3454

East Asian (EAS) AF: 0.237 AC: 1194 AN: 5032

South Asian (SAS) AF: 0.367 AC: 1739 AN: 4732

European-Finnish (FIN) AF: 0.403 AC: 4090 AN: 10140

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31681 AN: 67540

Other (OTH) AF: 0.385 AC: 803 AN: 2084

Alfa AF: 0.412 Hom.: 1648

Bravo AF: 0.361

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	0.40
PhyloP100		-1.2
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: rs3751549; hg19: chr15-101109227;