9-26996400-G-A

Position:

• chr9-26996400-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022901.3(LRRC19):​c.695C>T​(p.Ser232Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC19 NM_022901.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.733

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10084894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC19	NM_022901.3	c.695C>T	p.Ser232Leu	missense_variant	4/5	ENST00000380055.6	NP_075052.1
IFT74	NM_025103.4	c.587+6205G>A		intron_variant		ENST00000380062.10	NP_079379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC19	ENST00000380055.6	c.695C>T	p.Ser232Leu	missense_variant	4/5	1	NM_022901.3	ENSP00000369395	P1
IFT74	ENST00000380062.10	c.587+6205G>A		intron_variant		1	NM_025103.4	ENSP00000369402	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Apr 08, 2024

The c.695C>T (p.S232L) alteration is located in exon 4 (coding exon 3) of the LRRC19 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the serine (S) at amino acid position 232 to be replaced by a leucine (L). 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	0.068
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.36	N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.032
Sift	Benign	0.32	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.36		Loss of disorder (P = 0.0165);
MVP		0.59
MPC		0.020
ClinPred		0.069	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-26996398;