rs2298711

Variant names:

• chr18-59333237-T-A
• rs2298711
• NM_005570.4:c.1228A>T

Your query was ambiguous. Multiple possible variants found:

• chr18-59333237-T-A
• chr18-59333237-T-C

Variant summary

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

The NM_005570.4(LMAN1):​c.1228A>T​(p.Met410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,612,408 control chromosomes in the GnomAD database, including 14,988 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1064 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13924 hom.)
• Consequence: LMAN1 NM_005570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71
• Publications: 30 publications found

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]

LMAN1 Gene-Disease associations (from GenCC):

• factor V and factor VIII, combined deficiency of, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• combined deficiency of factor V and factor VIII

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267677 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014471412).
• BP6: Variant 18-59333237-T-A is Benign according to our data. Variant chr18-59333237-T-A is described in ClinVar as Benign. ClinVar VariationId is 259792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMAN1	NM_005570.4	c.1228A>T	p.Met410Leu	missense_variant	Exon 11 of 13	ENST00000251047.6	NP_005561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMAN1	ENST00000251047.6	c.1228A>T	p.Met410Leu	missense_variant	Exon 11 of 13	1	NM_005570.4	ENSP00000251047.4
LMAN1	ENST00000587918.1	n.455A>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000267677	ENST00000767581.1	n.288T>A		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000267677	ENST00000767578.1	n.232+8647T>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16131 AN: 151872 Hom.: 1065 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.121 AC: 30299 AN: 250040 AF XY: 0.119

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.134 AC: 196412 AN: 1460418 Hom.: 13924 Cov.: 33 AF XY: 0.133 AC XY: 96280 AN XY: 726538

African (AFR) AF: 0.0248 AC: 828 AN: 33428

American (AMR) AF: 0.176 AC: 7853 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2869 AN: 26102

East Asian (EAS) AF: 0.113 AC: 4472 AN: 39656

South Asian (SAS) AF: 0.0659 AC: 5675 AN: 86158

European-Finnish (FIN) AF: 0.120 AC: 6401 AN: 53354

Middle Eastern (MID) AF: 0.106 AC: 610 AN: 5764

European-Non Finnish (NFE) AF: 0.144 AC: 160305 AN: 1110988

Other (OTH) AF: 0.123 AC: 7399 AN: 60334

GnomAD4 genome AF: 0.106 AC: 16136 AN: 151990 Hom.: 1064 Cov.: 32 AF XY: 0.106 AC XY: 7903 AN XY: 74294

African (AFR) AF: 0.0292 AC: 1211 AN: 41480

American (AMR) AF: 0.152 AC: 2319 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3470

East Asian (EAS) AF: 0.103 AC: 535 AN: 5176

South Asian (SAS) AF: 0.0655 AC: 316 AN: 4826

European-Finnish (FIN) AF: 0.122 AC: 1284 AN: 10522

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9681 AN: 67950

Other (OTH) AF: 0.117 AC: 245 AN: 2102

Alfa AF: 0.128 Hom.: 417

Bravo AF: 0.107

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.148 AC: 569

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.135 AC: 1165

ExAC AF: 0.118 AC: 14345

Asia WGS AF: 0.0770 AC: 267 AN: 3472

EpiCase AF: 0.134

EpiControl AF: 0.131

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor V and factor VIII, combined deficiency of, type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.61
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.10
Sift	Benign	0.17	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.064
MutPred		0.14		Loss of MoRF binding (P = 0.0851);
MPC		0.19
ClinPred		0.0087	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.40
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2298711; hg19: chr18-57000469; COSMIC: COSV51828560; COSMIC: COSV51828560;