17-64859510-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_199340.5(LRRC37A3):c.4636T>C(p.Trp1546Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000673 in 148,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 30)
• Consequence: LRRC37A3 NM_199340.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

LRRC37A3 (HGNC:32427): (leucine rich repeat containing 37 member A3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC105376844 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRRC37A3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC37A3	NM_199340.5	c.4636T>C	p.Trp1546Arg	missense_variant	12/15	ENST00000584306.6
LOC105376844	XR_934912.4	n.177+9523A>G		intron_variant, non_coding_transcript_variant
LRRC37A3	NM_001303255.3	c.1990T>C	p.Trp664Arg	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC37A3	ENST00000584306.6	c.4636T>C	p.Trp1546Arg	missense_variant	12/15	1	NM_199340.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148630 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

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 Cov.: 33

GnomAD4 genome AF: 0.00000673 AC: 1 AN: 148630 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 72164

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

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

Jul 19, 2023

The c.4636T>C (p.W1546R) alteration is located in exon 11 (coding exon 9) of the LRRC37A3 gene. This alteration results from a T to C substitution at nucleotide position 4636, causing the tryptophan (W) at amino acid position 1546 to be replaced by an arginine (R). 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	0.70
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	19
Dann	Benign	0.86
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.83	T;T;T;T;.;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Pathogenic	0.87	D
REVEL	Benign	0.20
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.96	.;.;.;D;D;.
Vest4		0.48
MutPred		0.33		.;.;.;Gain of disorder (P = 0.0206);Gain of disorder (P = 0.0206);.;
MVP		0.38
ClinPred		0.76	D
GERP RS		1.3
Varity_R		0.41
gMVP		0.14

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: rs1403782505; hg19: chr17-62855628;