chr22-24588236-G-A

Position:

• chr22-24588236-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_207644.3(LRRC75B):​c.400C>T​(p.Arg134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: LRRC75B NM_207644.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011659771).
• BP6: Variant 22-24588236-G-A is Benign according to our data. Variant chr22-24588236-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2347196.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC75B	NM_207644.3	c.400C>T	p.Arg134Cys	missense_variant	3/4	ENST00000318753.13	NP_997527.2
GGT1	NM_013430.3	c.-429+4428G>A		intron_variant			NP_038347.2
LRRC75B	XM_005261600.4	c.*86C>T		downstream_gene_variant			XP_005261657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC75B	ENST00000318753.13	c.400C>T	p.Arg134Cys	missense_variant	3/4	1	NM_207644.3	ENSP00000320520.8
ENSG00000286070	ENST00000652248.1	n.*167+4428G>A		intron_variant				ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 45 AN: 246388 Hom.: 0 AF XY: 0.000165 AC XY: 22 AN XY: 133496

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000280

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1460800 Hom.: 0 Cov.: 30 AF XY: 0.000135 AC XY: 98 AN XY: 726598

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74482

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000237 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.069
Sift	Benign	0.14	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.10
MPC		0.21
ClinPred		0.0062	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.15

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: rs202133451; hg19: chr22-24984204; COSMIC: COSV99958872; COSMIC: COSV99958872;