17-46512917-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001006607.3(LRRC37A2):c.205C>T(p.Arg69Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (2 hom., cov: 16)
  • Exomes 𝑓: 0.000056 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A2 NM_001006607.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.218

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRRC37A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.018391252).
• BP6: Variant 17-46512917-C-T is Benign according to our data. Variant chr17-46512917-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2511250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC37A2	NM_001006607.3	c.205C>T	p.Arg69Trp	missense_variant	1/14	ENST00000576629.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC37A2	ENST00000576629.6	c.205C>T	p.Arg69Trp	missense_variant	1/14	5	NM_001006607.3	P1

Frequencies

GnomAD3 genomes AF: 0.000246 AC: 22 AN: 89580 Hom.: 2 Cov.: 16

Gnomad AFR AF: 0.000600

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000230

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000562 AC: 40 AN: 712028 Hom.: 3 Cov.: 5 AF XY: 0.0000486 AC XY: 17 AN XY: 350054

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.0000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000285

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000193

GnomAD4 genome AF: 0.000245 AC: 22 AN: 89694 Hom.: 2 Cov.: 16 AF XY: 0.000226 AC XY: 10 AN XY: 44336

Gnomad4 AFR AF: 0.000598

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000230

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ESP6500AA AF: 0.00126 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000133 AC: 10

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

Apr 13, 2023

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	0.069
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	6.2
Dann	Benign	0.88
DEOGEN2	Benign	0.00074	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0058	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.13	T;T
Polyphen		0.0010	B;B
Vest4		0.15
MVP		0.040
ClinPred		0.040	T
GERP RS		-0.14
Varity_R		0.036
gMVP		0.061

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: rs373973615; hg19: chr17-44590283;