rs35856562

Positions:

chr1-186182258-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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

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 -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 id is 781796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-186182258-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HMCN1	NM_031935.3 linkuse as main transcript	c.16385A>G	p.Gln5462Arg	missense_variant	105/107	ENST00000271588.9	NP_114141.2
HMCN1	XM_011510038.4 linkuse as main transcript	c.16034A>G	p.Gln5345Arg	missense_variant	104/106		XP_011508340.1
HMCN1	XM_017002437.2 linkuse as main transcript	c.14408A>G	p.Gln4803Arg	missense_variant	94/96		XP_016857926.1
HMCN1	XM_047431608.1 linkuse as main transcript	c.12209A>G	p.Gln4070Arg	missense_variant	82/84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9 linkuse as main transcript	c.16385A>G	p.Gln5462Arg	missense_variant	105/107	1	NM_031935.3	ENSP00000271588	P1	Q96RW7-1
HMCN1	ENST00000414277.1 linkuse as main transcript	c.410A>G	p.Gln137Arg	missense_variant	4/6	3		ENSP00000406205

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

GnomAD3 exomes

AF:

0.00225

AC:

564

AN:

250760

Hom.:

AF XY:

0.00212

AC XY:

287

AN XY:

135484

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 SAS exome

AF:

0.000261

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

Gnomad4 AFR exome

AF:

0.000778

Gnomad4 AMR exome

AF:

0.00309

Gnomad4 ASJ exome

AF:

0.00636

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00352

Gnomad4 OTH exome

AF:

0.00330

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152322

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00301

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00341

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

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

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

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;.

MutationTaster

Benign

0.91

N;N

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

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

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