chr15-100569699-T-C

Variant names:

• chr15-100569699-T-C
• rs141855950
• NM_001040616.3:c.1813A>G

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.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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M605I) has been classified as Uncertain significance.

• 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
• Publications: 12 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=0.0044367015).
• BP6: Variant 15-100569699-T-C is Benign according to our data. Variant chr15-100569699-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 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.1813A>G	p.Met605Val	missense	Exon 7 of 7	NP_001035706.2	Q8NG48-1
	LINS1	NM_001352508.2		c.1660A>G	p.Met554Val	missense	Exon 7 of 7	NP_001339437.1
	LINS1	NM_001352507.2		c.1066A>G	p.Met356Val	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.1813A>G	p.Met605Val	missense	Exon 7 of 7	ENSP00000318423.8	Q8NG48-1
	LINS1	ENST00000869609.1		c.1777A>G	p.Met593Val	missense	Exon 7 of 7	ENSP00000539668.1
	LINS1	ENST00000869606.1		c.1768A>G	p.Met590Val	missense	Exon 7 of 7	ENSP00000539665.1

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

GnomAD2 exomes AF: 0.00273 AC: 686 AN: 251096 AF XY: 0.00299

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 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

African (AFR) AF: 0.000358 AC: 12 AN: 33476

American (AMR) AF: 0.00150 AC: 67 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86214

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53414

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.00427 AC: 4744 AN: 1111862

Other (OTH) AF: 0.00278 AC: 168 AN: 60374

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

African (AFR) AF: 0.000554 AC: 23 AN: 41516

American (AMR) AF: 0.00144 AC: 22 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00369 Hom.: 8

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.0
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
Mutation Taster		=100/0	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: rs141855950; hg19: chr15-101109904; COSMIC: COSV106100670; COSMIC: COSV106100670;