rs606231152

Positions:

• chr7-156791581-A-G
• chr7-156791581-A-T

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+4808T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMBR1 NM_022458.4 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.60

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 7-156791581-A-G is Pathogenic according to our data. Variant chr7-156791581-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4906.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-156791581-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43). . 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+4808T>C		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+4808T>C		intron_variant		1	NM_022458.4	ENSP00000326604	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Triphalangeal thumb Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2008

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2022

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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant triphalangeal thumb (PMID: 18463159; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 295T>C. ClinVar contains an entry for this variant (Variation ID: 4906). 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

Aug 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.82

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: rs606231152; hg19: chr7-156584275;