1-186132407-A-G

Position:

chr1-186132407-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_031935.3(HMCN1):c.13310A>G(p.Gln4437Arg) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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, splice_region

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein
HMCN1	NM_031935.3 linkuse as main transcript	c.13310A>G	p.Gln4437Arg	missense_variant, splice_region_variant	86/107	ENST00000271588.9	NP_114141.2
HMCN1	XM_011510038.4 linkuse as main transcript	c.13310A>G	p.Gln4437Arg	missense_variant, splice_region_variant	86/106		XP_011508340.1
HMCN1	XM_017002437.2 linkuse as main transcript	c.11333A>G	p.Gln3778Arg	missense_variant, splice_region_variant	75/96		XP_016857926.1
HMCN1	XM_047431608.1 linkuse as main transcript	c.9134A>G	p.Gln3045Arg	missense_variant, splice_region_variant	63/84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9 linkuse as main transcript	c.13310A>G	p.Gln4437Arg	missense_variant, splice_region_variant	86/107	1	NM_031935.3	ENSP00000271588	P1	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

GnomAD3 exomes

AF:

0.380

AC:

93007

AN:

244910

Hom.:

19940

AF XY:

0.364

AC XY:

48087

AN XY:

132248

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 SAS exome

AF:

0.392

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

Gnomad4 AMR exome

AF:

0.561

Gnomad4 ASJ exome

AF:

0.315

Gnomad4 EAS exome

AF:

0.568

Gnomad4 SAS exome

AF:

0.390

Gnomad4 FIN exome

AF:

0.344

Gnomad4 NFE exome

AF:

0.252

Gnomad4 OTH exome

AF:

0.323

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

Gnomad4 AMR

AF:

0.459

Gnomad4 ASJ

AF:

0.311

Gnomad4 EAS

AF:

0.603

Gnomad4 SAS

AF:

0.404

Gnomad4 FIN

AF:

0.355

Gnomad4 NFE

AF:

0.261

Gnomad4 OTH

AF:

0.373

Alfa

AF:

0.299

Hom.:

17345

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

MutationTaster

Benign

5.9e-7

P;P

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

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