Genetic Variant LRRC75A:p.Pro174Leu (chr17-16444102-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_001113567.3(LRRC75A):c.521C>T(p.Pro174Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,098 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. 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. P174Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRRC75A
NM_001113567.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.406

Publications

0 publications found

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:

SNHG29 (HGNC:28619): (small nucleolar RNA host gene 29)

SNHG29 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=0.028336555).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113567.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC75A	NM_001113567.3	MANE Select	c.521C>T	p.Pro174Leu	missense	Exon 4 of 4	NP_001107039.1	Q8NAA5-1
LRRC75A	NM_207387.4		c.405C>T	p.Pro135Pro	synonymous	Exon 3 of 3	NP_997270.2	Q8NAA5-2
SNHG29	NR_027171.1		n.554+2972G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC75A	ENST00000470794.2	TSL:1 MANE Select	c.521C>T	p.Pro174Leu	missense	Exon 4 of 4	ENSP00000419502.1	Q8NAA5-1
LRRC75A	ENST00000409887.3	TSL:1	n.632C>T		non_coding_transcript_exon	Exon 3 of 3
SNHG29	ENST00000581361.5	TSL:1	n.181+3849G>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454098

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721994

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33344

American (AMR)

AF:

0.00

AC:

AN:

44330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25916

East Asian (EAS)

AF:

0.00

AC:

AN:

39460

South Asian (SAS)

AF:

0.00

AC:

AN:

85806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106630

Other (OTH)

AF:

0.00

AC:

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

0.059

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.023

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.70

M_CAP

Benign

0.0067

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.99

PhyloP100

0.41

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.067

Sift

Benign

0.13

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.047

MutPred

0.16

Loss of catalytic residue at P173 (P = 0.0121)

MVP

0.093

MPC

0.42

ClinPred

0.081

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.056

gMVP

0.22

Mutation Taster

=96/4

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