Genetic Variant NM_005570.4:c.956-3271G>A (chr18-59342224-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005570.4(LMAN1):c.956-3271G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 151,856 control chromosomes in the GnomAD database, including 39,686 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.72 ( 39686 hom., cov: 30)

Consequence

LMAN1
NM_005570.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.627

Publications

5 publications found

Variant links:

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

LMAN1 links:

ENSG00000267677 (HGNC:):

ENSG00000267677 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMAN1	NM_005570.4 link	c.956-3271G>A		intron_variant	Intron 8 of 12	ENST00000251047.6	NP_005561.1	P49257A0A024R2A7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMAN1	ENST00000251047.6 link	c.956-3271G>A		intron_variant	Intron 8 of 12	1	NM_005570.4	ENSP00000251047.4		P49257
ENSG00000267677	ENST00000767578.1 link	n.232+17634C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.720

AC:

109277

AN:

151738

Hom.:

39621

Cov.:

show subpopulations

Gnomad AFR

AF:

0.799

Gnomad AMI

AF:

0.521

Gnomad AMR

AF:

0.667

Gnomad ASJ

AF:

0.713

Gnomad EAS

AF:

0.505

Gnomad SAS

AF:

0.644

Gnomad FIN

AF:

0.648

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.721

Gnomad OTH

AF:

0.704

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.720

AC:

109402

AN:

151856

Hom.:

39686

Cov.:

AF XY:

0.713

AC XY:

52940

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.799

AC:

33140

AN:

41472

American (AMR)

AF:

0.667

AC:

10184

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.713

AC:

2471

AN:

3468

East Asian (EAS)

AF:

0.505

AC:

2606

AN:

5158

South Asian (SAS)

AF:

0.646

AC:

3099

AN:

4798

European-Finnish (FIN)

AF:

0.648

AC:

6821

AN:

10524

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.721

AC:

48928

AN:

67858

Other (OTH)

AF:

0.704

AC:

1490

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1517

3033

4550

6066

7583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.721

Hom.:

4891

Bravo

AF:

0.723

Asia WGS

AF:

0.616

AC:

2143

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

5.7

(source)

DANN

Benign

0.68

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over