rs587779752

Positions:

• chr7-156791474-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_022458.4(LMBR1):​c.423+4915C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMBR1 NM_022458.4 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:5
• Conservation: PhyloP100: 9.11

Genes affected

LMBR1 (HGNC:13243): (limb development membrane protein 1) This gene encodes a member of the LMBR1-like membrane protein family. Another member of this protein family has been shown to be a lipocalin transmembrane receptor. A highly conserved, cis-acting regulatory module for the sonic hedgehog gene is located within an intron of this gene. Consequently, disruption of this genic region can alter sonic hedgehog expression and affect limb patterning, but it is not known if this gene functions directly in limb development. Mutations and chromosomal deletions and rearrangements in this genic region are associated with acheiropody and preaxial polydactyly, which likely result from altered sonic hedgehog expression. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-156791474-G-A is Pathogenic according to our data. Variant chr7-156791474-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 126371.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMBR1	NM_022458.4	c.423+4915C>T		intron_variant		ENST00000353442.10	NP_071903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMBR1	ENST00000353442.10	c.423+4915C>T		intron_variant		1	NM_022458.4	ENSP00000326604	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, single submitter

Submissions by phenotype

Tibia, hypoplasia or aplasia of, with polydactyly Pathogenic:2

Pathogenic, no assertion criteria provided	research	Ahituv Lab, University of California San Francisco	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 28, 2014	- -

Triphalangeal thumb Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 28, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

This sequence change falls in intron 5 of the LMBR1 gene. It does not directly change the encoded amino acid sequence of the LMBR1 protein. This variant is present in population databases (rs587779752, gnomAD 0.1%). This variant has been observed in individual(s) with preaxial polydactyly and/or triphalangeal thumb (PMID: 24777739). It has also been observed to segregate with disease in related individuals. This variant is also known as ZRS 402C>T. ClinVar contains an entry for this variant (Variation ID: 126371). Studies have shown that this variant affects the ZPA regulatory sequence (ZRS) within intron 5 of the LMBR1 gene, which regulates the expression of certain genes that are important for limb development (PMID: 29651423). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Polydactyly of a triphalangeal thumb Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 28, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.77

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

Other links and lift over

dbSNP: rs587779752; hg19: chr7-156584168;