18-59333237-T-A

Variant names:

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

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M410V) has been classified as Uncertain significance.

• 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005570.4. 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
	LMAN1	NM_005570.4	MANE Select	c.1228A>T	p.Met410Leu	missense	Exon 11 of 13	NP_005561.1	P49257

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMAN1	ENST00000251047.6	TSL:1 MANE Select	c.1228A>T	p.Met410Leu	missense	Exon 11 of 13	ENSP00000251047.4	P49257
	LMAN1	ENST00000963587.1		c.1255A>T	p.Met419Leu	missense	Exon 11 of 13	ENSP00000633646.1
	LMAN1	ENST00000904707.1		c.1228A>T	p.Met410Leu	missense	Exon 11 of 13	ENSP00000574766.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Factor V and factor VIII, combined deficiency of, type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;