10-102109916-C-G

Variant names:

• chr10-102109916-C-G
• NM_001113407.3:c.648+5G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001113407.3(LDB1):​c.648+5G>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDB1 NM_001113407.3 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB1	NM_001113407.3	c.648+5G>C		splice_region_variant, intron_variant	Intron 7 of 10	ENST00000673968.1	NP_001106878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB1	ENST00000673968.1	c.648+5G>C		splice_region_variant, intron_variant	Intron 7 of 10		NM_001113407.3	ENSP00000501277.1
LDB1	ENST00000361198.9	c.540+5G>C		splice_region_variant, intron_variant	Intron 7 of 10	1		ENSP00000354616.5
LDB1	ENST00000425280.2	c.648+5G>C		splice_region_variant, intron_variant	Intron 7 of 10	5		ENSP00000392466.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 05, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: -32
DS_DL_spliceai		0.82		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-103869673;