chr18-59355522-T-C

Variant names:

• chr18-59355522-T-C
• rs1127220
• NM_005570.4:c.351A>G

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.351A>G​(p.Arg117Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,613,814 control chromosomes in the GnomAD database, including 52,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4241 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47904 hom.)
• Consequence: LMAN1 NM_005570.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.229
• Publications: 18 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 -16 ACMG points.

• BP6: Variant 18-59355522-T-C is Benign according to our data. Variant chr18-59355522-T-C is described in ClinVar as Benign. ClinVar VariationId is 259795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 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.351A>G	p.Arg117Arg	synonymous	Exon 2 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.351A>G	p.Arg117Arg	synonymous	Exon 2 of 13	ENSP00000251047.4	P49257
	LMAN1	ENST00000963587.1		c.351A>G	p.Arg117Arg	synonymous	Exon 2 of 13	ENSP00000633646.1
	LMAN1	ENST00000904707.1		c.351A>G	p.Arg117Arg	synonymous	Exon 2 of 13	ENSP00000574766.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35162 AN: 151964 Hom.: 4237 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.221 AC: 55578 AN: 251442 AF XY: 0.223

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.251 AC: 367525 AN: 1461732 Hom.: 47904 Cov.: 37 AF XY: 0.250 AC XY: 182112 AN XY: 727168

African (AFR) AF: 0.204 AC: 6837 AN: 33480

American (AMR) AF: 0.221 AC: 9899 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6629 AN: 26128

East Asian (EAS) AF: 0.0204 AC: 810 AN: 39692

South Asian (SAS) AF: 0.199 AC: 17132 AN: 86256

European-Finnish (FIN) AF: 0.202 AC: 10798 AN: 53414

Middle Eastern (MID) AF: 0.274 AC: 1578 AN: 5768

European-Non Finnish (NFE) AF: 0.270 AC: 299776 AN: 1111884

Other (OTH) AF: 0.233 AC: 14066 AN: 60390

GnomAD4 genome AF: 0.231 AC: 35170 AN: 152082 Hom.: 4241 Cov.: 32 AF XY: 0.227 AC XY: 16867 AN XY: 74350

African (AFR) AF: 0.205 AC: 8485 AN: 41478

American (AMR) AF: 0.249 AC: 3797 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3470

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5178

South Asian (SAS) AF: 0.184 AC: 888 AN: 4822

European-Finnish (FIN) AF: 0.196 AC: 2078 AN: 10582

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18168 AN: 67968

Other (OTH) AF: 0.232 AC: 489 AN: 2108

Alfa AF: 0.255 Hom.: 4564

Bravo AF: 0.232

Asia WGS AF: 0.116 AC: 405 AN: 3478

EpiCase AF: 0.268

EpiControl AF: 0.267

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
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.65
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1127220; hg19: chr18-57022754; COSMIC: COSV51825716; COSMIC: COSV51825716;