17-46546292-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001006607.3(LRRC37A2):c.3091T>C(p.Phe1031Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A2 NM_001006607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0430

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 -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRRC37A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009926349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC37A2	NM_001006607.3	c.3091T>C	p.Phe1031Leu	missense_variant	8/14	ENST00000576629.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC37A2	ENST00000576629.6	c.3091T>C	p.Phe1031Leu	missense_variant	8/14	5	NM_001006607.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 225 AN: 128398 Hom.: 0 Cov.: 20 FAILED QC

Gnomad AFR AF: 0.00380

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000611

Gnomad ASJ AF: 0.000921

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000439

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00289

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000763 AC: 533 AN: 698208 Hom.: 0 Cov.: 9 AF XY: 0.000781 AC XY: 290 AN XY: 371144

Gnomad4 AFR exome AF: 0.00491

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.000949

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.000233

Gnomad4 FIN exome AF: 0.000352

Gnomad4 NFE exome AF: 0.000790

Gnomad4 OTH exome AF: 0.000809

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00175 AC: 225 AN: 128498 Hom.: 0 Cov.: 20 AF XY: 0.00145 AC XY: 90 AN XY: 61908

Gnomad4 AFR AF: 0.00379

Gnomad4 AMR AF: 0.000610

Gnomad4 ASJ AF: 0.000921

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000439

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00135 Hom.: 0

ExAC AF: 0.0000618 AC: 4

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

Sep 01, 2021

The c.3091T>C (p.F1031L) alteration is located in exon 8 (coding exon 8) of the LRRC37A2 gene. This alteration results from a T to C substitution at nucleotide position 3091, causing the phenylalanine (F) at amino acid position 1031 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	Pathogenic	0.91
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.097	T;T
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0099	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.059	T;T
Polyphen		0.82	P;P
Vest4		0.32
MutPred		0.43		Loss of methylation at K1032 (P = 0.0424);Loss of methylation at K1032 (P = 0.0424);
MVP		0.092
ClinPred		0.12	T
GERP RS		2.6
Varity_R		0.18
gMVP		0.059

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: rs774129178; hg19: chr17-44623658; COSMIC: COSV61003871; COSMIC: COSV61003871;