Variant 9-26998165-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_022901.3(LRRC19):c.158A>C(p.Asp53Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

LRRC19
NM_022901.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

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]

LRRC19 links:

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]

IFT74 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.158A>C	p.Asp53Ala	missense_variant	3/5	ENST00000380055.6	NP_075052.1
IFT74	NM_025103.4 linkuse as main transcript	c.587+7970T>G		intron_variant		ENST00000380062.10	NP_079379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC19	ENST00000380055.6 linkuse as main transcript	c.158A>C	p.Asp53Ala	missense_variant	3/5	1	NM_022901.3	ENSP00000369395	P1
IFT74	ENST00000380062.10 linkuse as main transcript	c.587+7970T>G		intron_variant		1	NM_025103.4	ENSP00000369402	P1	Q96LB3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.158A>C (p.D53A) alteration is located in exon 3 (coding exon 2) of the LRRC19 gene. This alteration results from a A to C substitution at nucleotide position 158, causing the aspartic acid (D) at amino acid position 53 to be replaced by an alanine (A). 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

Pathogenic

0.58

BayesDel_addAF

Benign

0.0080

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.097

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.59

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0060

Sift4G

Benign

0.065

Polyphen

1.0

Vest4

0.52

MutPred

0.61

Loss of sheet (P = 0.1158);

MVP

0.87

MPC

0.095

ClinPred

0.94

GERP RS

4.4

Varity_R

0.26

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over