rs141855950

Positions:

• chr15-100569699-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040616.3(LINS1):​c.1813A>G​(p.Met605Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,613,844 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (13 hom.)
• Consequence: LINS1 NM_001040616.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044367015).
• BP6: Variant 15-100569699-T-C is Benign according to our data. Variant chr15-100569699-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 211382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-100569699-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00249 (379/152234) while in subpopulation NFE AF= 0.00425 (289/68018). AF 95% confidence interval is 0.00385. There are 2 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.1813A>G	p.Met605Val	missense_variant	7/7	ENST00000314742.13	NP_001035706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LINS1	ENST00000314742.13	c.1813A>G	p.Met605Val	missense_variant	7/7	5	NM_001040616.3	ENSP00000318423.8
LINS1	ENST00000559169.1	n.2088A>G		non_coding_transcript_exon_variant	2/2	2
LINS1	ENST00000560783.1	n.190+3952A>G		intron_variant		5		ENSP00000474128.1

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00273 AC: 686 AN: 251096 Hom.: 3 AF XY: 0.00299 AC XY: 406 AN XY: 135712

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00494

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00352 AC: 5142 AN: 1461610 Hom.: 13 Cov.: 34 AF XY: 0.00351 AC XY: 2550 AN XY: 727086

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00427

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74424

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00425

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00370 Hom.: 5

Bravo AF: 0.00244

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LINS1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 17, 2015	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.2
DANN	Benign	0.38
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.038
Sift	Benign	0.28	T
Sift4G	Benign	0.60	T
Polyphen		0.0060	B
Vest4		0.11
MVP		0.15
MPC		0.024
ClinPred		0.0025	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs141855950; hg19: chr15-101109904;