chr18-59354506-AAC-A

Variant names:

• chr18-59354506-AAC-A
• rs3835325
• NM_005570.4:c.539+11_539+12delGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005570.4(LMAN1):​c.539+11_539+12delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,430,510 control chromosomes in the GnomAD database, including 17,657 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1582 hom., cov: 30)
  • Exomes 𝑓: 0.15 (16075 hom.)
• Consequence: LMAN1 NM_005570.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.412
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 18-59354506-AAC-A is Benign according to our data. Variant chr18-59354506-AAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 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.539+11_539+12delGT		intron	N/A	NP_005561.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMAN1	ENST00000251047.6	TSL:1 MANE Select	c.539+11_539+12delGT		intron	N/A	ENSP00000251047.4
	LMAN1	ENST00000963587.1		c.539+11_539+12delGT		intron	N/A	ENSP00000633646.1
	LMAN1	ENST00000904707.1		c.539+11_539+12delGT		intron	N/A	ENSP00000574766.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20717 AN: 152030 Hom.: 1577 Cov.: 30

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.150 AC: 37392 AN: 249170 AF XY: 0.153

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.0272

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.153 AC: 195436 AN: 1278364 Hom.: 16075 AF XY: 0.154 AC XY: 99568 AN XY: 645594

African (AFR) AF: 0.0510 AC: 1544 AN: 30296

American (AMR) AF: 0.166 AC: 7323 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3464 AN: 24868

East Asian (EAS) AF: 0.0194 AC: 752 AN: 38788

South Asian (SAS) AF: 0.149 AC: 12273 AN: 82116

European-Finnish (FIN) AF: 0.163 AC: 8624 AN: 52862

Middle Eastern (MID) AF: 0.124 AC: 670 AN: 5418

European-Non Finnish (NFE) AF: 0.162 AC: 153315 AN: 945492

Other (OTH) AF: 0.137 AC: 7471 AN: 54354

GnomAD4 genome AF: 0.136 AC: 20723 AN: 152146 Hom.: 1582 Cov.: 30 AF XY: 0.136 AC XY: 10087 AN XY: 74368

African (AFR) AF: 0.0612 AC: 2542 AN: 41548

American (AMR) AF: 0.171 AC: 2610 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 532 AN: 3468

East Asian (EAS) AF: 0.0287 AC: 149 AN: 5188

South Asian (SAS) AF: 0.145 AC: 699 AN: 4816

European-Finnish (FIN) AF: 0.165 AC: 1740 AN: 10568

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12025 AN: 67958

Other (OTH) AF: 0.128 AC: 269 AN: 2106

Alfa AF: 0.155 Hom.: 359

Bravo AF: 0.132

Asia WGS AF: 0.0860 AC: 297 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=99/1	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: rs3835325; hg19: chr18-57021738; COSMIC: COSV51825926; COSMIC: COSV51825926;