22-24586050-C-T

Variant names:

• chr22-24586050-C-T
• rs200284399
• NM_207644.3:c.784G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207644.3(LRRC75B):​c.784G>A​(p.Gly262Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,611,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: LRRC75B NM_207644.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

Genes affected

LRRC75B (HGNC:33155): (leucine rich repeat containing 75B) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286070 (HGNC:):

GGT1 (HGNC:4250): (gamma-glutamyltransferase 1) The enzyme encoded by this gene is a type I gamma-glutamyltransferase that catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. The enzyme is composed of a heavy chain and a light chain, which are derived from a single precursor protein. It is expressed in tissues involved in absorption and secretion and may contribute to the etiology of diabetes and other metabolic disorders. Multiple alternatively spliced variants have been identified. There are a number of related genes present on chromosomes 20 and 22, and putative pseudogenes for this gene on chromosomes 2, 13, and 22. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038352102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC75B	NM_207644.3	c.784G>A	p.Gly262Ser	missense_variant	Exon 4 of 4	ENST00000318753.13	NP_997527.2
GGT1	NM_013430.3	c.-429+2242C>T		intron_variant	Intron 1 of 15		NP_038347.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC75B	ENST00000318753.13	c.784G>A	p.Gly262Ser	missense_variant	Exon 4 of 4	1	NM_207644.3	ENSP00000320520.8
ENSG00000286070	ENST00000652248.1	n.*167+2242C>T		intron_variant	Intron 5 of 19			ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000159 AC: 39 AN: 244948 Hom.: 0 AF XY: 0.000165 AC XY: 22 AN XY: 133306

Gnomad AFR exome AF: 0.000780

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000726

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.0000946 AC: 138 AN: 1459334 Hom.: 0 Cov.: 31 AF XY: 0.0000978 AC XY: 71 AN XY: 726142

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74492

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000972 Hom.: 0

Bravo AF: 0.000434

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000190 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.784G>A (p.G262S) alteration is located in exon 4 (coding exon 4) of the LRRC75B gene. This alteration results from a G to A substitution at nucleotide position 784, causing the glycine (G) at amino acid position 262 to be replaced by a serine (S). 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	0.081
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.099
Sift	Benign	0.85	T
Sift4G	Benign	0.78	T
Polyphen		0.77	P
Vest4		0.12
MVP		0.31
MPC		0.17
ClinPred		0.016	T
GERP RS		2.8
Varity_R		0.036
gMVP		0.57

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: rs200284399; hg19: chr22-24982018;