chr15-100569393-C-T

Variant names:

• chr15-100569393-C-T
• rs74039425
• NM_001040616.3:c.2119G>A

Variant summary

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

The NM_001040616.3(LINS1):​c.2119G>A​(p.Gly707Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,613,926 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G707G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: LINS1 NM_001040616.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.262
• 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=0.003466487).
• BP6: Variant 15-100569393-C-T is Benign according to our data. Variant chr15-100569393-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129484.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 = 0.00205 (312/152156) while in subpopulation AFR AF = 0.00689 (286/41514). AF 95% confidence interval is 0.00623. There are 2 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040616.3. 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.2119G>A	p.Gly707Arg	missense	Exon 7 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352508.2		c.1966G>A	p.Gly656Arg	missense	Exon 7 of 7	NP_001339437.1
	LINS1	NM_001352507.2		c.1372G>A	p.Gly458Arg	missense	Exon 8 of 8	NP_001339436.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINS1	ENST00000314742.13	TSL:5 MANE Select	c.2119G>A	p.Gly707Arg	missense	Exon 7 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000869609.1		c.2083G>A	p.Gly695Arg	missense	Exon 7 of 7	ENSP00000539668.1
	LINS1	ENST00000869606.1		c.2074G>A	p.Gly692Arg	missense	Exon 7 of 7	ENSP00000539665.1

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 311 AN: 152038 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00689

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000684 AC: 172 AN: 251362 AF XY: 0.000567

Gnomad AFR exome AF: 0.00777

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461770 Hom.: 1 Cov.: 32 AF XY: 0.000202 AC XY: 147 AN XY: 727200

African (AFR) AF: 0.00550 AC: 184 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111896

Other (OTH) AF: 0.000464 AC: 28 AN: 60394

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152156 Hom.: 2 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74388

African (AFR) AF: 0.00689 AC: 286 AN: 41514

American (AMR) AF: 0.00131 AC: 20 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000747 Hom.: 1

Bravo AF: 0.00211

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	LINS1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.26
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.084
Sift	Benign	0.16	T
Sift4G	Benign	0.37	T
Polyphen		0.17	B
Vest4		0.13
MutPred		0.65		Loss of sheet (P = 0.0228)
MVP		0.11
MPC		0.033
ClinPred		0.013	T
GERP RS		4.9
Varity_R		0.070
gMVP		0.37
Mutation Taster		=99/1	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: rs74039425; hg19: chr15-101109598;