7-100153882-A-G

Position:

• chr7-100153882-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001008395.4(LAMTOR4):​c.218A>G​(p.His73Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAMTOR4 NM_001008395.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

Genes affected

LAMTOR4 (HGNC:33772): (late endosomal/lysosomal adaptor, MAPK and MTOR activator 4) Contributes to guanyl-nucleotide exchange factor activity and molecular adaptor activity. Involved in several processes, including cellular response to amino acid stimulus; positive regulation of TOR signaling; and protein localization to lysosome. Located in lysosome. Part of Ragulator complex. [provided by Alliance of Genome Resources, Apr 2022]

LAMTOR4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMTOR4	NM_001008395.4	c.218A>G	p.His73Arg	missense_variant	4/4	ENST00000341942.10	NP_001008396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMTOR4	ENST00000341942.10	c.218A>G	p.His73Arg	missense_variant	4/4	1	NM_001008395.4	ENSP00000343118.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430740 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 24, 2023

The c.218A>G (p.H73R) alteration is located in exon 4 (coding exon 4) of the LAMTOR4 gene. This alteration results from a A to G substitution at nucleotide position 218, causing the histidine (H) at amino acid position 73 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	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T;.;T;.
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.0	D;.;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.024	D;.;.;.;.
Sift4G	Benign	0.17	T;T;T;T;.
Polyphen		0.80	P;.;.;.;.
Vest4		0.73
MutPred		0.52		Gain of MoRF binding (P = 0.013);.;.;.;.;
MVP		0.36
MPC		0.65
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.80
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs539134040; hg19: chr7-99751505;