rs145145735

Variant names:

• chr15-100574155-G-A
• rs145145735
• NM_001040616.3:c.718C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001352507.2(LINS1):​c.-30C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,613,688 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: LINS1 NM_001352507.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.45
• Publications: 5 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 (MetaRNN=0.0037718415).
• BP6: Variant 15-100574155-G-A is Benign according to our data. Variant chr15-100574155-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00378 (575/152226) while in subpopulation AFR AF = 0.0134 (556/41546). AF 95% confidence interval is 0.0125. There are 1 homozygotes in GnomAd4. There are 271 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352507.2. 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.718C>T	p.Arg240Trp	missense	Exon 5 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352507.2		c.-30C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 8	NP_001339436.1
	LINS1	NM_001352508.2		c.673C>T	p.Arg225Trp	missense	Exon 5 of 7	NP_001339437.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINS1	ENST00000314742.13	TSL:5 MANE Select	c.718C>T	p.Arg240Trp	missense	Exon 5 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000561308.5	TSL:1	c.718C>T	p.Arg240Trp	missense	Exon 5 of 5	ENSP00000454200.1	Q8NG48-2
	LINS1	ENST00000869609.1		c.682C>T	p.Arg228Trp	missense	Exon 5 of 7	ENSP00000539668.1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152108 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00116 AC: 289 AN: 250020 AF XY: 0.000796

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000452 AC: 660 AN: 1461462 Hom.: 3 Cov.: 36 AF XY: 0.000396 AC XY: 288 AN XY: 726992

African (AFR) AF: 0.0157 AC: 527 AN: 33472

American (AMR) AF: 0.000962 AC: 43 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111668

Other (OTH) AF: 0.00113 AC: 68 AN: 60380

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152226 Hom.: 1 Cov.: 33 AF XY: 0.00364 AC XY: 271 AN XY: 74414

African (AFR) AF: 0.0134 AC: 556 AN: 41546

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00162 Hom.: 3

Bravo AF: 0.00458

ESP6500AA AF: 0.0153 AC: 67

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.4
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.036	D
Polyphen		0.85	P
Vest4		0.18
MVP		0.77
MPC		0.081
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.13
Mutation Taster		=98/2	polymorphism

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: rs145145735; hg19: chr15-101114360; COSMIC: COSV99042925; COSMIC: COSV99042925;