Genetic Variant LDB1:p.Val42Met (chr10-102111438-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001113407.3(LDB1):c.124G>A(p.Val42Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000909 in 1,429,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000091 ( 0 hom. )

Consequence

LDB1
NM_001113407.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

Variant links:

Genes affected

LDB1 (HGNC:6532): (LIM domain binding 1) Enables LIM domain binding activity; RNA polymerase II-specific DNA-binding transcription factor binding activity; and enzyme binding activity. Involved in negative regulation of transcription, DNA-templated and positive regulation of transcription by RNA polymerase II. Located in chromatin. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

LDB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB1	NM_001113407.3 link	c.124G>A	p.Val42Met	missense_variant	Exon 2 of 11	ENST00000673968.1	NP_001106878.1	Q86U70-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDB1	ENST00000673968.1 link	c.124G>A	p.Val42Met	missense_variant	Exon 2 of 11		NM_001113407.3	ENSP00000501277.1	Q86U70-1
LDB1	ENST00000361198.9 link	c.16G>A	p.Val6Met	missense_variant	Exon 2 of 11	1		ENSP00000354616.5	Q86U70-2
LDB1	ENST00000425280.2 link	c.124G>A	p.Val42Met	missense_variant	Exon 2 of 11	5		ENSP00000392466.2	A0A6E1WJ75

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000874

AC:

AN:

228802

Hom.:

AF XY:

0.0000163

AC XY:

AN XY:

122832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000387

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000960

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000909

AC:

AN:

1429508

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

707318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000101

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>A (p.V42M) alteration is located in exon 2 (coding exon 2) of the LDB1 gene. This alteration results from a G to A substitution at nucleotide position 124, causing the valine (V) at amino acid position 42 to be replaced by a methionine (M). 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

0.10

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.0073

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.55

.;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.53

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.086

T;D

Sift4G

Benign

0.36

T;T

Polyphen

0.99

.;D

Vest4

0.72

MutPred

0.42

.;Gain of disorder (P = 0.1036);

MVP

0.50

MPC

1.4

ClinPred

0.56

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over