rs2298712

Variant names:

• chr18-59333071-G-A
• rs2298712
• NM_005570.4:c.1374+20C>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.1374+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,592,906 control chromosomes in the GnomAD database, including 78,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9402 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69295 hom.)
• Consequence: LMAN1 NM_005570.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.770
• Publications: 6 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 (BayesDel_noAF=-0.83).
• BP6: Variant 18-59333071-G-A is Benign according to our data. Variant chr18-59333071-G-A is described in ClinVar as Benign. ClinVar VariationId is 259793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 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.1374+20C>T		intron	N/A	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.1374+20C>T		intron	N/A	ENSP00000251047.4	P49257
	LMAN1	ENST00000963587.1		c.1401+20C>T		intron	N/A	ENSP00000633646.1
	LMAN1	ENST00000904707.1		c.1374+20C>T		intron	N/A	ENSP00000574766.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52165 AN: 151746 Hom.: 9385 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.308 AC: 76999 AN: 249612 AF XY: 0.313

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.273

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.306 AC: 441094 AN: 1441042 Hom.: 69295 Cov.: 28 AF XY: 0.308 AC XY: 221398 AN XY: 718108

African (AFR) AF: 0.457 AC: 15081 AN: 32974

American (AMR) AF: 0.190 AC: 8480 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8972 AN: 25988

East Asian (EAS) AF: 0.258 AC: 10187 AN: 39528

South Asian (SAS) AF: 0.375 AC: 32101 AN: 85624

European-Finnish (FIN) AF: 0.320 AC: 17031 AN: 53270

Middle Eastern (MID) AF: 0.314 AC: 1792 AN: 5710

European-Non Finnish (NFE) AF: 0.300 AC: 328084 AN: 1093720

Other (OTH) AF: 0.325 AC: 19366 AN: 59616

GnomAD4 genome AF: 0.344 AC: 52221 AN: 151864 Hom.: 9402 Cov.: 32 AF XY: 0.341 AC XY: 25334 AN XY: 74222

African (AFR) AF: 0.445 AC: 18420 AN: 41406

American (AMR) AF: 0.251 AC: 3831 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1220 AN: 3466

East Asian (EAS) AF: 0.268 AC: 1384 AN: 5164

South Asian (SAS) AF: 0.388 AC: 1867 AN: 4810

European-Finnish (FIN) AF: 0.328 AC: 3452 AN: 10534

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21107 AN: 67926

Other (OTH) AF: 0.324 AC: 684 AN: 2114

Alfa AF: 0.328 Hom.: 3298

Bravo AF: 0.340

Asia WGS AF: 0.357 AC: 1240 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.52
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2298712; hg19: chr18-57000303; COSMIC: COSV51826224; COSMIC: COSV51826224;