Genetic Variant LRRC34:p.Ser249Arg (chr3-169800667-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001172779.2(LRRC34):c.745A>C(p.Ser249Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,527,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. S249G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

LRRC34
NM_001172779.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.68

Publications

77 publications found

Variant links:

Genes affected

LRRC34 (HGNC:28408): (leucine rich repeat containing 34) Predicted to be involved in cell differentiation. Predicted to be located in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

LRRC34 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.092829436).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172779.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC34	NM_001172779.2	MANE Select	c.745A>C	p.Ser249Arg	missense	Exon 7 of 11	NP_001166250.1	Q8IZ02-2
LRRC34	NM_001363888.2		c.562A>C	p.Ser188Arg	missense	Exon 7 of 11	NP_001350817.1	G3V115
LRRC34	NM_001370608.1		c.559A>C	p.Ser187Arg	missense	Exon 7 of 11	NP_001357537.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC34	ENST00000446859.7	TSL:2 MANE Select	c.745A>C	p.Ser249Arg	missense	Exon 7 of 11	ENSP00000414635.1	Q8IZ02-2
LRRC34	ENST00000522526.6	TSL:1	c.657+3386A>C		intron	N/A	ENSP00000429278.2	Q8IZ02-3
LRRC34	ENST00000895445.1		c.661A>C	p.Ser221Arg	missense	Exon 6 of 10	ENSP00000565504.1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000181

AC:

AN:

132890

AF XY:

0.000138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000832

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000421

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000433

AC:

595

AN:

1375412

Hom.:

Cov.:

AF XY:

0.000455

AC XY:

309

AN XY:

679158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31386

American (AMR)

AF:

0.0000850

AC:

AN:

35314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25114

East Asian (EAS)

AF:

0.00

AC:

AN:

35542

South Asian (SAS)

AF:

0.00

AC:

AN:

78534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5188

European-Non Finnish (NFE)

AF:

0.000537

AC:

576

AN:

1072916

Other (OTH)

AF:

0.000278

AC:

AN:

57548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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

AF:

0.000178

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41346

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00000179

Hom.:

26576

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000669

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0018

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.29

M_CAP

Benign

0.029

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.75

PhyloP100

2.7

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.051

Sift

Benign

0.033

Sift4G

Benign

0.12

Polyphen

0.71

Vest4

0.26

MutPred

0.27

Gain of catalytic residue at S188 (P = 0.0484)

MVP

0.46

MPC

0.24

ClinPred

0.19

GERP RS

3.4

Varity_R

0.23

gMVP

0.63

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over