18-59333237-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005570.4(LMAN1):​c.1228A>G​(p.Met410Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M410L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMAN1 NM_005570.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056961954).

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>G	p.Met410Val	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>G	p.Met410Val	missense	Exon 11 of 13	ENSP00000251047.4	P49257
	LMAN1	ENST00000963587.1		c.1255A>G	p.Met419Val	missense	Exon 11 of 13	ENSP00000633646.1
	LMAN1	ENST00000904707.1		c.1228A>G	p.Met410Val	missense	Exon 11 of 13	ENSP00000574766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.25
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.23		Loss of helix (P = 0.0237)
MVP		0.40
MPC		0.20
ClinPred		0.066	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.37
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;