17-46515039-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_001006607.3(LRRC37A2):c.2327G>A(p.Arg776His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (10 hom., cov: 6)
  • Exomes 𝑓: 0.00052 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A2 NM_001006607.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.619

Genes affected

LRRC37A2 (HGNC:32404): (leucine rich repeat containing 37 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARL17A (HGNC:24096): (ADP ribosylation factor like GTPase 17A) Predicted to enable GTP binding activity. Predicted to be involved in intracellular protein transport and vesicle-mediated transport. Predicted to be located in Golgi apparatus. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRRC37A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011043578).
• BP6: Variant 17-46515039-G-A is Benign according to our data. Variant chr17-46515039-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3120593.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC37A2	NM_001006607.3	c.2327G>A	p.Arg776His	missense_variant	1/14	ENST00000576629.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC37A2	ENST00000576629.6	c.2327G>A	p.Arg776His	missense_variant	1/14	5	NM_001006607.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 80 AN: 71854 Hom.: 10 Cov.: 6 FAILED QC

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00299

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000107

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000523 AC: 362 AN: 691640 Hom.: 29 Cov.: 4 AF XY: 0.000537 AC XY: 183 AN XY: 340712

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.000198

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00573

Gnomad4 SAS exome AF: 0.0000831

Gnomad4 FIN exome AF: 0.0000598

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.000582

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00111 AC: 80 AN: 71934 Hom.: 10 Cov.: 6 AF XY: 0.00107 AC XY: 38 AN XY: 35630

Gnomad4 AFR AF: 0.00256

Gnomad4 AMR AF: 0.00121

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00300

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000108

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00160 Hom.: 0

ExAC AF: 0.000166 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.078
Dann	Benign	0.69
DEOGEN2	Benign	0.0011	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00074	N
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.41	T;T
Polyphen		0.0	B;B
Vest4		0.068
MVP		0.014
ClinPred		0.0076	T
GERP RS		-1.4
Varity_R		0.018
gMVP		0.051

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: rs199621736; hg19: chr17-44592405;