chr9-26997956-G-C

Position:

• chr9-26997956-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000380055.6(LRRC19):​c.367C>G​(p.Leu123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LRRC19 ENST00000380055.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

LRRC19 (HGNC:23379): (leucine rich repeat containing 19) Predicted to enable signaling receptor activity. Acts upstream of or within positive regulation of NIK/NF-kappaB signaling. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IFT74 (HGNC:21424): (intraflagellar transport 74) This gene encodes a core intraflagellar transport (IFT) protein which belongs to a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. This protein, together with intraflagellar transport protein 81, binds and transports tubulin within cilia and is required for ciliogenesis. Naturally occurring mutations in this gene are associated with amyotrophic lateral sclerosis--frontotemporal dementia and Bardet-Biedl Syndrome. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC19	NM_022901.3	c.367C>G	p.Leu123Val	missense_variant	3/5	ENST00000380055.6	NP_075052.1
IFT74	NM_025103.4	c.587+7761G>C		intron_variant		ENST00000380062.10	NP_079379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC19	ENST00000380055.6	c.367C>G	p.Leu123Val	missense_variant	3/5	1	NM_022901.3	ENSP00000369395.5
IFT74	ENST00000380062.10	c.587+7761G>C		intron_variant		1	NM_025103.4	ENSP00000369402.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.367C>G (p.L123V) alteration is located in exon 3 (coding exon 2) of the LRRC19 gene. This alteration results from a C to G substitution at nucleotide position 367, causing the leucine (L) at amino acid position 123 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.70
Sift	Benign	0.044	D
Sift4G	Uncertain	0.011	D
Polyphen		0.91	P
Vest4		0.42
MutPred		0.66		Gain of methylation at K122 (P = 0.039);
MVP		0.93
MPC		0.13
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs944683606; hg19: chr9-26997954;