rs33926449

chr18-59359129-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005570.4(LMAN1):c.116T>C(p.Val39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0835 in 1,613,990 control chromosomes in the GnomAD database, including 6,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (797 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5357 hom.)
• Consequence: LMAN1 NM_005570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.253

Genes affected

LMAN1 (HGNC:6631): (lectin, mannose binding 1) The protein encoded by this gene is a membrane mannose-specific lectin that cycles between the endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment, and cis-Golgi, functioning as a cargo receptor for glycoprotein transport. The protein has an N-terminal signal sequence, a calcium-dependent and pH-sensitive carbohydrate recognition domain, a stalk region that functions in oligomerization, a transmembrane domain, and a short cytoplasmic domain required for organelle targeting. Allelic variants of this gene are associated with the autosomal recessive disorder combined factor V-factor VIII deficiency. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016942322).
• BP6: Variant 18-59359129-A-G is Benign according to our data. Variant chr18-59359129-A-G is described in ClinVar as [Benign]. Clinvar id is 259791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMAN1	NM_005570.4	c.116T>C	p.Val39Ala	missense_variant	1/13	ENST00000251047.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMAN1	ENST00000251047.6	c.116T>C	p.Val39Ala	missense_variant	1/13	1	NM_005570.4	P1
LMAN1	ENST00000587561.1	n.137T>C		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14178 AN: 152134 Hom.: 796 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0775

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.0685 AC: 17210 AN: 251136 Hom.: 791 AF XY: 0.0678 AC XY: 9208 AN XY: 135868

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0473

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.0353

Gnomad NFE exome AF: 0.0863

Gnomad OTH exome AF: 0.0776

GnomAD4 exome AF: 0.0825 AC: 120535 AN: 1461738 Hom.: 5357 Cov.: 33 AF XY: 0.0814 AC XY: 59200 AN XY: 727188

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0512

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0365

Gnomad4 NFE exome AF: 0.0890

Gnomad4 OTH exome AF: 0.0844

GnomAD4 genome AF: 0.0932 AC: 14186 AN: 152252 Hom.: 797 Cov.: 32 AF XY: 0.0891 AC XY: 6633 AN XY: 74448

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0774

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0941 Hom.: 880

Bravo AF: 0.0984

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0929 AC: 358

ESP6500AA AF: 0.129 AC: 567

ESP6500EA AF: 0.0865 AC: 744

ExAC AF: 0.0698 AC: 8474

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0960

EpiControl AF: 0.0959

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Factor V and factor VIII, combined deficiency of, type 1 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	4.1
Dann	Benign	0.43
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00047	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.24
ClinPred		0.0020	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.018
gMVP		0.31

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: rs33926449; hg19: chr18-57026361;