1-186132407-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_031935.3(HMCN1):c.13310A>G(p.Gln4437Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,604,574 control chromosomes in the GnomAD database, including 83,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 13644 hom., cov: 32)

Exomes 𝑓: 0.29 ( 70261 hom. )

Consequence

HMCN1
NM_031935.3 missense

Scores

Splicing: ADA: 0.1729

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 8.50

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.746112E-5).

BP6

Variant 1-186132407-A-G is Benign according to our data. Variant chr1-186132407-A-G is described in ClinVar as [Benign]. Clinvar id is 294262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCN1	NM_031935.3 link	c.13310A>G	p.Gln4437Arg	missense_variant	Exon 86 of 107	ENST00000271588.9	NP_114141.2	Q96RW7-1
HMCN1	XM_011510038.4 link	c.13310A>G	p.Gln4437Arg	missense_variant	Exon 86 of 106		XP_011508340.1	Q96RW7-2
HMCN1	XM_017002437.2 link	c.11333A>G	p.Gln3778Arg	missense_variant, splice_region_variant	Exon 75 of 96		XP_016857926.1
HMCN1	XM_047431608.1 link	c.9134A>G	p.Gln3045Arg	missense_variant, splice_region_variant	Exon 63 of 84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9 link	c.13310A>G	p.Gln4437Arg	missense_variant	Exon 86 of 107	1	NM_031935.3	ENSP00000271588.4		Q96RW7-1

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59768

AN:

151826

Hom.:

13586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.458

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.603

Gnomad SAS

AF:

0.405

Gnomad FIN

AF:

0.355

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.261

Gnomad OTH

AF:

0.365

GnomAD2 exomes

AF:

0.380

AC:

93007

AN:

244910

AF XY:

0.364

show subpopulations

Gnomad AFR exome

AF:

0.600

Gnomad AMR exome

AF:

0.571

Gnomad ASJ exome

AF:

0.323

Gnomad EAS exome

AF:

0.605

Gnomad FIN exome

AF:

0.350

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

AF:

0.294

AC:

427079

AN:

1452626

Hom.:

70261

Cov.:

AF XY:

0.295

AC XY:

213312

AN XY:

722632

show subpopulations

Gnomad4 AFR exome

AF:

0.609

AC:

20275

AN:

33270

Gnomad4 AMR exome

AF:

0.561

AC:

24759

AN:

44158

Gnomad4 ASJ exome

AF:

0.315

AC:

8178

AN:

26000

Gnomad4 EAS exome

AF:

0.568

AC:

22370

AN:

39408

Gnomad4 SAS exome

AF:

0.390

AC:

33356

AN:

85532

Gnomad4 FIN exome

AF:

0.344

AC:

18292

AN:

53112

Gnomad4 NFE exome

AF:

0.252

AC:

278581

AN:

1105448

Gnomad4 Remaining exome

AF:

0.323

AC:

19366

AN:

59946

Heterozygous variant carriers

13197

26394

39591

52788

65985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

9830

19660

29490

39320

49150

<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:

0.394

AC:

59886

AN:

151948

Hom.:

13644

Cov.:

AF XY:

0.399

AC XY:

29603

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.587

AC:

0.587153

AN:

0.587153

Gnomad4 AMR

AF:

0.459

AC:

0.458968

AN:

0.458968

Gnomad4 ASJ

AF:

0.311

AC:

0.310772

AN:

0.310772

Gnomad4 EAS

AF:

0.603

AC:

0.602559

AN:

0.602559

Gnomad4 SAS

AF:

0.404

AC:

0.403742

AN:

0.403742

Gnomad4 FIN

AF:

0.355

AC:

0.355233

AN:

0.355233

Gnomad4 NFE

AF:

0.261

AC:

0.260551

AN:

0.260551

Gnomad4 OTH

AF:

0.373

AC:

0.372633

AN:

0.372633

Heterozygous variant carriers

1651

3302

4954

6605

8256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.317

Hom.:

28433

Bravo

AF:

0.416

TwinsUK

AF:

0.247

AC:

917

ALSPAC

AF:

0.244

AC:

941

ESP6500AA

AF:

0.579

AC:

2553

ESP6500EA

AF:

0.263

AC:

2258

ExAC

AF:

0.370

AC:

44817

Asia WGS

AF:

0.536

AC:

1862

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Age related macular degeneration 1

Benign:3

Jan 12, 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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.58

MetaRNN

Benign

0.000077

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.65

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.14

Sift

Benign

0.35

Sift4G

Uncertain

0.0020

Polyphen

0.73

Vest4

0.24

MPC

0.26

ClinPred

0.021

GERP RS

5.4

Varity_R

0.59

gMVP

0.58

Mutation Taster

=87/13

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.17

dbscSNV1_RF

Benign

0.43

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over