17-64859888-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_199340.5(LRRC37A3):c.4258A>G(p.Asn1420Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1420S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRRC37A3 NM_199340.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.827

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRRC37A3
• BP4: Computational evidence support a benign effect (MetaRNN=0.07728246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC37A3	NM_199340.5	c.4258A>G	p.Asn1420Asp	missense_variant	12/15	ENST00000584306.6
LOC105376844	XR_934912.4	n.177+9901T>C		intron_variant, non_coding_transcript_variant
LRRC37A3	NM_001303255.3	c.1612A>G	p.Asn538Asp	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC37A3	ENST00000584306.6	c.4258A>G	p.Asn1420Asp	missense_variant	12/15	1	NM_199340.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Mar 06, 2023

The c.4258A>G (p.N1420D) alteration is located in exon 11 (coding exon 9) of the LRRC37A3 gene. This alteration results from a A to G substitution at nucleotide position 4258, causing the asparagine (N) at amino acid position 1420 to be replaced by an aspartic acid (D). 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	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	6.2
Dann	Benign	0.57
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.65	T;T;T;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
REVEL	Benign	0.047
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.88	.;.;.;P;P
Vest4		0.082
MutPred		0.15		.;.;.;Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.040
ClinPred		0.12	T
GERP RS		-2.5
Varity_R		0.12
gMVP		0.042

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-62856006;