dbSNP rs2093858580: LRRC75A:p.Gln5Leu (chr17-16491977-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001113567.3(LRRC75A):c.14A>T(p.Gln5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000676 in 147,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. Q5E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Consequence

LRRC75A
NM_001113567.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

Variant links:

Genes affected

LRRC75A (HGNC:32403): (leucine rich repeat containing 75A) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LRRC75A links:

LOC124903936 (HGNC:):

LOC124903936 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1781969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC75A	NM_001113567.3 link	c.14A>T	p.Gln5Leu	missense_variant	Exon 1 of 4	ENST00000470794.2	NP_001107039.1	Q8NAA5-1B7ZMA3
LRRC75A	NM_207387.4 link	c.14A>T	p.Gln5Leu	missense_variant	Exon 1 of 3		NP_997270.2	Q8NAA5-2
LRRC75A	XM_047435962.1 link	c.14A>T	p.Gln5Leu	missense_variant	Exon 1 of 4		XP_047291918.1
LOC124903936	XR_007065641.1 link	n.1605+4531T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC75A	ENST00000470794.2 link	c.14A>T	p.Gln5Leu	missense_variant	Exon 1 of 4	1	NM_001113567.3	ENSP00000419502.1		Q8NAA5-1
LRRC75A	ENST00000409083.7 link	c.14A>T	p.Gln5Leu	missense_variant	Exon 1 of 3	2		ENSP00000386504.3		Q8NAA5-2

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147850

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72008

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40542

American (AMR)

AF:

0.00

AC:

AN:

14948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5006

South Asian (SAS)

AF:

0.000209

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66494

Other (OTH)

AF:

0.00

AC:

AN:

2032

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.14A>T (p.Q5L) alteration is located in exon 1 (coding exon 1) of the LRRC75A gene. This alteration results from a A to T substitution at nucleotide position 14, causing the glutamine (Q) at amino acid position 5 to be replaced by a leucine (L). 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

0.30

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0020

.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.61

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;L

PhyloP100

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.12

Sift

Benign

0.056

T;T

Sift4G

Benign

0.077

T;T

Polyphen

0.97

D;P

Vest4

0.23

MutPred

0.19

Gain of catalytic residue at M1 (P = 0.0265);Gain of catalytic residue at M1 (P = 0.0265);

MVP

0.043

MPC

1.1

ClinPred

0.65

GERP RS

1.9

PromoterAI

0.0049

Neutral

(source)

Varity_R

0.089

gMVP

0.55

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over