Genetic Variant NM_207644.3:c.844C>T (chr22-24585990-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_207644.3(LRRC75B):c.844C>T(p.Leu282Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L282I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LRRC75B
NM_207644.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.405

Publications

0 publications found

Variant links:

Genes affected

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

LRRC75B links:

ENSG00000286070 (HGNC:):

ENSG00000286070 links:

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]

GGT1 Gene-Disease associations (from GenCC):

gamma-glutamyl transpeptidase deficiency
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

GGT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030564457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207644.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC75B	NM_207644.3	MANE Select	c.844C>T	p.Leu282Phe	missense	Exon 4 of 4	NP_997527.2	Q2VPJ9-1
	GGT1	NM_013430.3		c.-429+2182G>A		intron	N/A	NP_038347.2	P19440-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC75B	ENST00000318753.13	TSL:1 MANE Select	c.844C>T	p.Leu282Phe	missense	Exon 4 of 4	ENSP00000320520.8	Q2VPJ9-1
ENSG00000286070	ENST00000652248.1		n.*167+2182G>A		intron	N/A	ENSP00000499210.1
LRRC75B	ENST00000935984.1		c.1237C>T	p.Leu413Phe	missense	Exon 6 of 6	ENSP00000606043.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458374

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725644

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111836

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.3

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.012

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.52

M_CAP

Benign

0.014

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.92

PhyloP100

0.41

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.74

REVEL

Benign

0.034

Sift

Benign

0.27

Sift4G

Benign

0.47

Polyphen

0.0010

Vest4

0.031

MutPred

0.18

Loss of sheet (P = 0.0817)

MVP

0.11

MPC

0.16

ClinPred

0.039

GERP RS

-1.4

Varity_R

0.035

gMVP

0.17

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over