rs10254391

Variant names:

• chr7-156791873-G-C
• rs10254391
• NM_022458.4:c.423+4516C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022458.4(LMBR1):​c.423+4516C>G variant causes a intron change. The variant allele was found at a frequency of 0.307 in 151,912 control chromosomes in the GnomAD database, including 7,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.31 (7465 hom., cov: 32)
• Consequence: LMBR1 NM_022458.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.35
• Publications: 4 publications found

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]

LMBR1 Gene-Disease associations (from GenCC):

• polydactyly of a triphalangeal thumb

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• acheiropody

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• hypoplastic tibiae-postaxial polydactyly syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• laurin-Sandrow syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• triphalangeal thumb-polysyndactyly syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-156791873-G-C is Benign according to our data. Variant chr7-156791873-G-C is described in ClinVar as Benign. ClinVar VariationId is 768220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMBR1	NM_022458.4	MANE Select	c.423+4516C>G		intron	N/A	NP_071903.2
	LMBR1	NM_001350953.2		c.423+4516C>G		intron	N/A	NP_001337882.1	Q8WVP7-3
	LMBR1	NM_001363409.2		c.423+4516C>G		intron	N/A	NP_001350338.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMBR1	ENST00000353442.10	TSL:1 MANE Select	c.423+4516C>G		intron	N/A	ENSP00000326604.7	Q8WVP7-1
	LMBR1	ENST00000415428.5	TSL:1	c.417+4516C>G		intron	N/A	ENSP00000408256.1	H0Y6V6
	LMBR1	ENST00000875405.1		c.423+4516C>G		intron	N/A	ENSP00000545464.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46581 AN: 151792 Hom.: 7455 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.287

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

GnomAD4 genome AF: 0.307 AC: 46638 AN: 151912 Hom.: 7465 Cov.: 32 AF XY: 0.313 AC XY: 23219 AN XY: 74240

African (AFR) AF: 0.302 AC: 12527 AN: 41416

American (AMR) AF: 0.386 AC: 5892 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3468

East Asian (EAS) AF: 0.560 AC: 2891 AN: 5164

South Asian (SAS) AF: 0.256 AC: 1231 AN: 4818

European-Finnish (FIN) AF: 0.370 AC: 3899 AN: 10544

Middle Eastern (MID) AF: 0.208 AC: 60 AN: 288

European-Non Finnish (NFE) AF: 0.274 AC: 18626 AN: 67944

Other (OTH) AF: 0.286 AC: 603 AN: 2106

Alfa AF: 0.297 Hom.: 886

Bravo AF: 0.312

Asia WGS AF: 0.350 AC: 1219 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		6.3
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10254391; hg19: chr7-156584567;