chr17-46297322-A-T

Variant names:

• chr17-46297322-A-T
• rs1216520046
• NM_014834.4:c.2189A>T

Variant summary

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

The NM_014834.4(LRRC37A):​c.2189A>T​(p.Lys730Ile) 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 0.000028 (0 hom., cov: 14)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A NM_014834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27
• Publications: 0 publications found

Genes affected

LRRC37A (HGNC:29069): (leucine rich repeat containing 37A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARL17B (HGNC:32387): (ADP ribosylation factor like GTPase 17B) 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=0.10527086).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014834.4. 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
	LRRC37A	NM_014834.4	MANE Select	c.2189A>T	p.Lys730Ile	missense	Exon 1 of 14	NP_055649.4	A6NMS7
	ARL17B	NM_001103154.2		c.*21+2204T>A		intron	N/A	NP_001096624.1
	ARL17B	NM_001352769.1		c.*21+2204T>A		intron	N/A	NP_001339698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC37A	ENST00000320254.5	TSL:1 MANE Select	c.2189A>T	p.Lys730Ile	missense	Exon 1 of 14	ENSP00000326324.5	A6NMS7
	LRRC37A	ENST00000393465.7	TSL:5	c.2189A>T	p.Lys730Ile	missense	Exon 1 of 12	ENSP00000377108.2	A8MUI5
	LRRC37A	ENST00000496930.5	TSL:2	c.-277-2472A>T		intron	N/A	ENSP00000437021.1	E9PP10

Frequencies

GnomAD3 genomes AF: 0.0000280 AC: 3 AN: 107276 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.0000313

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: 0.0000386

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000233 AC: 22 AN: 942210 Hom.: 0 Cov.: 15 AF XY: 0.0000329 AC XY: 16 AN XY: 485586

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

African (AFR) AF: 0.0000424 AC: 1 AN: 23604

American (AMR) AF: 0.0000367 AC: 1 AN: 27272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21818

East Asian (EAS) AF: 0.00 AC: 0 AN: 19618

South Asian (SAS) AF: 0.0000289 AC: 2 AN: 69202

European-Finnish (FIN) AF: 0.0000228 AC: 1 AN: 43880

Middle Eastern (MID) AF: 0.000324 AC: 1 AN: 3088

European-Non Finnish (NFE) AF: 0.0000217 AC: 15 AN: 691746

Other (OTH) AF: 0.0000238 AC: 1 AN: 41982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000160472), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000280 AC: 3 AN: 107276 Hom.: 0 Cov.: 14 AF XY: 0.0000397 AC XY: 2 AN XY: 50386

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

African (AFR) AF: 0.0000313 AC: 1 AN: 31962

American (AMR) AF: 0.00 AC: 0 AN: 9128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2816

East Asian (EAS) AF: 0.00 AC: 0 AN: 912

South Asian (SAS) AF: 0.00 AC: 0 AN: 3134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000386 AC: 2 AN: 51848

Other (OTH) AF: 0.00 AC: 0 AN: 1484

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000102688), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.87
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.046
Sift	Benign	0.083	T
Sift4G	Benign	0.15	T
Polyphen		0.79	P
Vest4		0.17
MutPred		0.33		Loss of ubiquitination at K730 (P = 0.0019)
MVP		0.043
ClinPred		0.30	T
GERP RS		0.86
Varity_R		0.31
gMVP		0.077

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: rs1216520046; hg19: chr17-44374688;