15-100569017-G-T

Variant names:

• chr15-100569017-G-T
• rs3751548
• NM_001040616.3:c.*221C>A

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.*221C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 394,006 control chromosomes in the GnomAD database, including 32,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11480 hom., cov: 26)
  • Exomes 𝑓: 0.40 (21353 hom.)
• Consequence: LINS1 NM_001040616.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.17
• 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=-0.94).
• BP6: Variant 15-100569017-G-T is Benign according to our data. Variant chr15-100569017-G-T is described in ClinVar as [Benign]. Clinvar id is 1236013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.*221C>A		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.*221C>A		3_prime_UTR_variant	Exon 7 of 7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000560783.1	n.191-3752C>A		intron_variant	Intron 1 of 3	5		ENSP00000474128.1
LINS1	ENST00000559169.1	n.*218C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 56832 AN: 150518 Hom.: 11478 Cov.: 26

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.385

GnomAD4 exome AF: 0.404 AC: 98247 AN: 243372 Hom.: 21353 Cov.: 0 AF XY: 0.401 AC XY: 51871 AN XY: 129298

African (AFR) AF: 0.267 AC: 1977 AN: 7398

American (AMR) AF: 0.228 AC: 2175 AN: 9540

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 2711 AN: 7654

East Asian (EAS) AF: 0.233 AC: 3645 AN: 15672

South Asian (SAS) AF: 0.373 AC: 10854 AN: 29118

European-Finnish (FIN) AF: 0.381 AC: 4056 AN: 10648

Middle Eastern (MID) AF: 0.371 AC: 384 AN: 1036

European-Non Finnish (NFE) AF: 0.452 AC: 67028 AN: 148394

Other (OTH) AF: 0.389 AC: 5417 AN: 13912

GnomAD4 genome AF: 0.377 AC: 56849 AN: 150634 Hom.: 11480 Cov.: 26 AF XY: 0.373 AC XY: 27413 AN XY: 73426

African (AFR) AF: 0.274 AC: 11218 AN: 40996

American (AMR) AF: 0.274 AC: 4155 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1390 AN: 3458

East Asian (EAS) AF: 0.237 AC: 1201 AN: 5062

South Asian (SAS) AF: 0.367 AC: 1746 AN: 4762

European-Finnish (FIN) AF: 0.402 AC: 4126 AN: 10262

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

European-Non Finnish (NFE) AF: 0.469 AC: 31702 AN: 67622

Other (OTH) AF: 0.384 AC: 801 AN: 2088

Alfa AF: 0.265 Hom.: 657

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

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.48
DANN	Benign	0.83
PhyloP100		-2.2
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: rs3751548; hg19: chr15-101109222;