1-70039454-T-G

Variant names:

• chr1-70039454-T-G
• rs1135401780
• NM_001370785.2:c.3630T>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001370785.2(LRRC7):​c.3630T>G​(p.Tyr1210*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC7 NM_001370785.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192

Genes affected

LRRC7 (HGNC:18531): (leucine rich repeat containing 7) Predicted to be involved in several processes, including establishment or maintenance of epithelial cell apical/basal polarity; positive regulation of neuron projection development; and receptor clustering. Located in several cellular components, including centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LRRC7-AS1 (HGNC:40843): (LRRC7 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC7	NM_001370785.2	c.3630T>G	p.Tyr1210*	stop_gained	Exon 21 of 27	ENST00000651989.2	NP_001357714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC7	ENST00000651989.2	c.3630T>G	p.Tyr1210*	stop_gained	Exon 21 of 27		NM_001370785.2	ENSP00000498937.2
LRRC7	ENST00000415775.2	c.1368T>G	p.Tyr456*	stop_gained	Exon 15 of 21	1		ENSP00000394867.2
LRRC7	ENST00000310961.9	c.3531T>G	p.Tyr1177*	stop_gained	Exon 22 of 27	5		ENSP00000309245.4
LRRC7	ENST00000651217.1	n.3546T>G		non_coding_transcript_exon_variant	Exon 19 of 25

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Uncertain:1

Aug 01, 2017

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo LOF variant identified in a male patient with IQ 70, absence epilepsy during first years, obesity, muscle and joint pain, migraine. LRRC7 encodes a brain-specific scaffold protein in postsynaptic densities and contains a PDZ domain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	0.016
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.43
GERP RS		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1135401780; hg19: chr1-70505137;