16-67367221-A-C

Position:

• chr16-67367221-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018296.6(LRRC36):​c.959A>C​(p.His320Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (1 hom., cov: 32)
• Consequence: LRRC36 NM_018296.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

Genes affected

LRRC36 (HGNC:25615): (leucine rich repeat containing 36)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27600285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC36	NM_018296.6	c.959A>C	p.His320Pro	missense_variant	8/14	ENST00000329956.11	NP_060766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC36	ENST00000329956.11	c.959A>C	p.His320Pro	missense_variant	8/14	1	NM_018296.6	ENSP00000329943.6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152244 Hom.: 1 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74388

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: 0.0000294

Gnomad4 OTH AF: 0.00

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

May 02, 2024

The c.959A>C (p.H320P) alteration is located in exon 8 (coding exon 8) of the LRRC36 gene. This alteration results from a A to C substitution at nucleotide position 959, causing the histidine (H) at amino acid position 320 to be replaced by a proline (P). 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	0.11
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.0043	T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N;N;D
REVEL	Benign	0.15
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.87	P;P;.
Vest4		0.46
MutPred		0.27		Loss of loop (P = 0.0374);.;.;
MVP		0.53
MPC		0.79
ClinPred		0.75	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.44

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: rs1412172856; hg19: chr16-67401124;