7-156681152-C-G

Position:

• chr7-156681152-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022458.4(LMBR1):​c.*2926G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 452,244 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: LMBR1 NM_022458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0210

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-156681152-C-G is Benign according to our data. Variant chr7-156681152-C-G is described in ClinVar as [Benign]. Clinvar id is 359370.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (240/152144) while in subpopulation NFE AF= 0.00234 (159/68000). AF 95% confidence interval is 0.00204. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMBR1	NM_022458.4	c.*2926G>C		3_prime_UTR_variant	17/17	ENST00000353442.10	NP_071903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMBR1	ENST00000353442.10	c.*2926G>C		3_prime_UTR_variant	17/17	1	NM_022458.4	ENSP00000326604	P1
LMBR1	ENST00000430825.3	n.266-578G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 241 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00148 AC: 200 AN: 134828 Hom.: 2 AF XY: 0.00138 AC XY: 101 AN XY: 73332

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000244

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000550

Gnomad FIN exome AF: 0.000735

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00169 AC: 508 AN: 300100 Hom.: 2 Cov.: 0 AF XY: 0.00160 AC XY: 274 AN XY: 171264

Gnomad4 AFR exome AF: 0.000972

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.0000936

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000746

Gnomad4 FIN exome AF: 0.000862

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74356

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00161

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polydactyly of a triphalangeal thumb Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.93
DANN	Benign	0.57

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: rs148658727; hg19: chr7-156473846;