17-46514964-T-G

Variant names:

• chr17-46514964-T-G
• rs1175569023
• NM_001006607.3:c.2252T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001006607.3(LRRC37A2):​c.2252T>G​(p.Leu751Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (1 hom., cov: 8)
  • Exomes 𝑓: 0.0000086 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A2 NM_001006607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.135
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1433562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC37A2	NM_001006607.3	MANE Select	c.2252T>G	p.Leu751Arg	missense	Exon 1 of 14	NP_001006608.2	A6NM11
	LRRC37A2	NM_001385803.1		c.2252T>G	p.Leu751Arg	missense	Exon 1 of 14	NP_001372732.1
	ARL17A	NM_001288812.1		c.*21+2130A>C		intron	N/A	NP_001275741.1	Q8IVW1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC37A2	ENST00000576629.6	TSL:5 MANE Select	c.2252T>G	p.Leu751Arg	missense	Exon 1 of 14	ENSP00000459551.1	A6NM11
	LRRC37A2	ENST00000706058.1		c.2252T>G	p.Leu751Arg	missense	Exon 1 of 8	ENSP00000516210.1	A0A994J7J8
	LRRC37A2	ENST00000705813.1		c.-88-2398T>G		intron	N/A	ENSP00000516171.1	A0A994J7H6

Frequencies

GnomAD3 genomes AF: 0.0000414 AC: 3 AN: 72426 Hom.: 1 Cov.: 8

Gnomad AFR AF: 0.000136

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000379 AC: 5 AN: 132008 AF XY: 0.0000145

Gnomad AFR exome AF: 0.000484

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000862 AC: 6 AN: 695672 Hom.: 2 Cov.: 4 AF XY: 0.00000292 AC XY: 1 AN XY: 342958

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000271 AC: 6 AN: 22122

American (AMR) AF: 0.00 AC: 0 AN: 30904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10076

East Asian (EAS) AF: 0.00 AC: 0 AN: 33558

South Asian (SAS) AF: 0.00 AC: 0 AN: 36764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1522

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 497872

Other (OTH) AF: 0.00 AC: 0 AN: 29356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000414 AC: 3 AN: 72426 Hom.: 1 Cov.: 8 AF XY: 0.0000558 AC XY: 2 AN XY: 35870

African (AFR) AF: 0.000136 AC: 3 AN: 22106

American (AMR) AF: 0.00 AC: 0 AN: 7506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1268

East Asian (EAS) AF: 0.00 AC: 0 AN: 4038

South Asian (SAS) AF: 0.00 AC: 0 AN: 1834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 28006

Other (OTH) AF: 0.00 AC: 0 AN: 854

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.3
DANN	Benign	0.48
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.14
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.71	T
Polyphen		0.88	P
Vest4		0.49
MutPred		0.21		Gain of solvent accessibility (P = 0.1071)
MVP		0.061
ClinPred		0.079	T
GERP RS		-0.97
Varity_R		0.12
gMVP		0.091
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1175569023; hg19: chr17-44592330;