rs121434382

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_031935.3(HMCN1):c.16034A>G(p.Gln5345Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00103 in 1,614,054 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

HMCN1
NM_031935.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:1

Conservation

PhyloP100: 3.94

Publications

17 publications found

Variant links:

Genes affected

HMCN1 (HGNC:19194): (hemicentin 1) This gene encodes a large extracellular member of the immunoglobulin superfamily. A similar protein in C. elegans forms long, fine tracks at specific extracellular sites that are involved in many processes such as stabilization of the germline syncytium, anchorage of mechanosensory neurons to the epidermis, and organization of hemidesmosomes in the epidermis. Mutations in this gene may be associated with age-related macular degeneration. [provided by RefSeq, Jul 2008]

HMCN1 Gene-Disease associations (from GenCC):

age related macular degeneration 1
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

HMCN1 links:

ENSG00000294274 (HGNC:):

ENSG00000294274 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035621405).

BP6

Variant 1-186178506-A-G is Benign according to our data. Variant chr1-186178506-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2205.

BS2

High AC in GnomAd4 at 104 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCN1	NM_031935.3 link	c.16034A>G	p.Gln5345Arg	missense_variant	Exon 104 of 107	ENST00000271588.9	NP_114141.2	Q96RW7-1
HMCN1	XM_017002437.2 link	c.14057A>G	p.Gln4686Arg	missense_variant	Exon 93 of 96		XP_016857926.1
HMCN1	XM_047431608.1 link	c.11858A>G	p.Gln3953Arg	missense_variant	Exon 81 of 84		XP_047287564.1
HMCN1	XM_011510038.4 link	c.15944-3662A>G		intron_variant	Intron 103 of 105		XP_011508340.1	Q96RW7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HMCN1	ENST00000271588.9 link	c.16034A>G	p.Gln5345Arg	missense_variant	Exon 104 of 107	1	NM_031935.3	ENSP00000271588.4	Q96RW7-1
HMCN1	ENST00000414277.1 link	c.320-3662A>G		intron_variant	Intron 3 of 5	3		ENSP00000406205.1	Q5TCP6
ENSG00000294274	ENST00000722342.1 link	n.239-40573T>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000733

AC:

184

AN:

250876

AF XY:

0.000819

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.00107

AC:

1565

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

744

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00135

AC:

1497

AN:

1111912

Other (OTH)

AF:

0.000546

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

175

263

350

438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152302

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41562

American (AMR)

AF:

0.000784

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00118

Hom.:

Bravo

AF:

0.000740

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00125

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Age related macular degeneration 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MACULAR DEGENERATION, AGE-RELATED, 1, SUSCEPTIBILITY TO

Other:1

Apr 01, 2007

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.18

Eigen_PC

Benign

0.045

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.74

M_CAP

Benign

0.039

MetaRNN

Benign

0.036

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.46

PhyloP100

3.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.47

Sift

Benign

0.86

Sift4G

Benign

0.40

Polyphen

0.0050

Vest4

0.28

MVP

0.78

MPC

0.21

ClinPred

0.022

GERP RS

4.7

Varity_R

0.27

gMVP

0.62

Mutation Taster

=92/8

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over