NM_031935.3:c.16385A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_031935.3(HMCN1):c.16385A>G(p.Gln5462Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,613,514 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 11 hom. )

Consequence

HMCN1
NM_031935.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.00

Publications

9 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011597693).

BP6

Variant 1-186182258-A-G is Benign according to our data. Variant chr1-186182258-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 781796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 286 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCN1	NM_031935.3 link	c.16385A>G	p.Gln5462Arg	missense_variant	Exon 105 of 107	ENST00000271588.9	NP_114141.2	Q96RW7-1
HMCN1	XM_011510038.4 link	c.16034A>G	p.Gln5345Arg	missense_variant	Exon 104 of 106		XP_011508340.1	Q96RW7-2
HMCN1	XM_017002437.2 link	c.14408A>G	p.Gln4803Arg	missense_variant	Exon 94 of 96		XP_016857926.1
HMCN1	XM_047431608.1 link	c.12209A>G	p.Gln4070Arg	missense_variant	Exon 82 of 84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HMCN1	ENST00000271588.9 link	c.16385A>G	p.Gln5462Arg	missense_variant	Exon 105 of 107	1	NM_031935.3	ENSP00000271588.4	Q96RW7-1
HMCN1	ENST00000414277.1 link	c.410A>G	p.Gln137Arg	missense_variant	Exon 4 of 6	3		ENSP00000406205.1	Q5TCP6
ENSG00000294274	ENST00000722342.1 link	n.238+39498T>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00225

AC:

564

AN:

250760

AF XY:

0.00212

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.00557

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00312

Gnomad OTH exome

AF:

0.00588

GnomAD4 exome

AF:

0.00308

AC:

4496

AN:

1461192

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2226

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.000778

AC:

AN:

33432

American (AMR)

AF:

0.00309

AC:

138

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00636

AC:

166

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000313

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00352

AC:

3910

AN:

1111492

Other (OTH)

AF:

0.00330

AC:

199

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

211

422

632

843

1054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.00188

AC:

286

AN:

152322

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000697

AC:

AN:

41580

American (AMR)

AF:

0.00170

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00301

AC:

205

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.00318

Hom.:

Bravo

AF:

0.00215

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00217

AC:

264

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00385

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Age related macular degeneration 1

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

-0.23

N;.

PhyloP100

2.0

PrimateAI

Benign

0.34

PROVEAN

Benign

1.7

N;N

REVEL

Benign

0.17

Sift

Benign

0.95

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0020

B;.

Vest4

0.20

MVP

0.77

MPC

0.28

ClinPred

0.012

GERP RS

3.1

Varity_R

0.037

gMVP

0.39

Mutation Taster

=98/2

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