rs1127220

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr18-59355522-T-C
• chr18-59355522-T-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: 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 18-59355522-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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMAN1	NM_005570.4	c.351A>G	p.Arg117Arg	synonymous_variant	Exon 2 of 13	ENST00000251047.6	NP_005561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMAN1	ENST00000251047.6	c.351A>G	p.Arg117Arg	synonymous_variant	Exon 2 of 13	1	NM_005570.4	ENSP00000251047.4
LMAN1	ENST00000587561.1	n.372A>G		non_coding_transcript_exon_variant	Exon 2 of 5	2
ENSG00000267677	ENST00000767578.1	n.232+30932T>C		intron_variant	Intron 1 of 1
ENSG00000267677	ENST00000767579.1	n.842+3720T>C		intron_variant	Intron 1 of 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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor V and factor VIII, combined deficiency of, type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;