Genetic Variant LBHD1:p.Arg208Ile (chr11-62664889-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024099.5(LBHD1):c.623G>T(p.Arg208Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

LBHD1
NM_024099.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.45

Publications

0 publications found

Variant links:

Genes affected

LBHD1 (HGNC:28351): (LBH domain containing 1) This gene shares three exons in common with another gene, chromosome 11 open reading frame 98 (GeneID:102288414), but the encoded protein uses a reading frame that is different from that of the chromosome 11 open reading frame 98 gene. [provided by RefSeq, Nov 2017]

LBHD1 links:

C11orf98 (HGNC:51238): (chromosome 11 open reading frame 98) This gene shares three exons in common with another gene, LBH domain containing 1 (GeneID:79081), but the encoded protein uses a reading frame that is different from that of the LBH domain containing 1 gene. [provided by RefSeq, Nov 2017]

C11orf98 links:

ENSG00000255432 (HGNC:):

ENSG00000255432 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBHD1	NM_024099.5 link	c.623G>T	p.Arg208Ile	missense_variant	Exon 5 of 7	ENST00000354588.8	NP_077004.2	Q9BQE6-2A0A024R584
C11orf98	NM_001286086.2 link	c.124G>T	p.Asp42Tyr	missense_variant	Exon 2 of 4	ENST00000524958.6	NP_001273015.1	E9PRG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LBHD1	ENST00000354588.8 link	c.623G>T	p.Arg208Ile	missense_variant	Exon 5 of 7	1	NM_024099.5	ENSP00000346600.3	Q9BQE6-2
C11orf98	ENST00000524958.6 link	c.124G>T	p.Asp42Tyr	missense_variant	Exon 2 of 4	2	NM_001286086.2	ENSP00000432523.2	E9PRG8
ENSG00000255432	ENST00000528405.1 link	c.124G>T	p.Asp42Tyr	missense_variant	Exon 2 of 4	4		ENSP00000435188.1	E9PLD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436704

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32980

American (AMR)

AF:

0.00

AC:

AN:

40330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25584

East Asian (EAS)

AF:

0.00

AC:

AN:

38554

South Asian (SAS)

AF:

0.00

AC:

AN:

82994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099818

Other (OTH)

AF:

0.0000168

AC:

AN:

59366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.623G>T (p.R208I) alteration is located in exon 5 (coding exon 4) of the LBHD1 gene. This alteration results from a G to T substitution at nucleotide position 623, causing the arginine (R) at amino acid position 208 to be replaced by an isoleucine (I). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.77

D;D;D

MetaSVM

Benign

-0.90

PhyloP100

5.5

PROVEAN

Pathogenic

-7.6

D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Vest4

0.98

MVP

0.33

MPC

1.2

ClinPred

0.98

GERP RS

3.9

PromoterAI

0.0026

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.57

gMVP

0.77

Mutation Taster

=75/25

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over