NM_015541.3:c.70C>T

Variant names:

• chr3-66500338-G-A
• rs1403626
• NM_015541.3:c.70C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015541.3(LRIG1):​c.70C>T​(p.Leu24Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L24V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 20 publications found

Genes affected

LRIG1 (HGNC:17360): (leucine rich repeats and immunoglobulin like domains 1) Predicted to act upstream of or within several processes, including innervation; otolith morphogenesis; and sensory perception of sound. Predicted to be located in plasma membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27394682).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015541.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	NM_015541.3	MANE Select	c.70C>T	p.Leu24Phe	missense	Exon 1 of 19	NP_056356.2
	LRIG1	NM_001377344.1		c.70C>T	p.Leu24Phe	missense	Exon 1 of 18	NP_001364273.1
	LRIG1	NM_001377345.1		c.-563+755C>T		intron	N/A	NP_001364274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	ENST00000273261.8	TSL:1 MANE Select	c.70C>T	p.Leu24Phe	missense	Exon 1 of 19	ENSP00000273261.3
	LRIG1	ENST00000383703.3	TSL:1	c.70C>T	p.Leu24Phe	missense	Exon 1 of 20	ENSP00000373208.3
	LRIG1	ENST00000498287.5	TSL:4	n.171+755C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151324 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1345108 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 665892

African (AFR) AF: 0.00 AC: 0 AN: 28210

American (AMR) AF: 0.00 AC: 0 AN: 27416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22798

East Asian (EAS) AF: 0.00 AC: 0 AN: 32018

South Asian (SAS) AF: 0.00 AC: 0 AN: 74288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4848

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062276

Other (OTH) AF: 0.00 AC: 0 AN: 55568

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151324 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73868

African (AFR) AF: 0.0000485 AC: 2 AN: 41252

American (AMR) AF: 0.00 AC: 0 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5018

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67750

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 3163

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.44	N
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.097
Sift	Benign	0.13	T
Sift4G	Benign	0.44	T
Polyphen		0.91	P
Vest4		0.32
MutPred		0.39		Loss of disorder (P = 0.0508)
MVP		0.27
MPC		0.32
ClinPred		0.45	T
GERP RS		3.1
Varity_R		0.098
gMVP		0.46
Mutation Taster		=81/19	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: rs1403626; hg19: chr3-66550762;