rs121434382

Positions:

chr1-186178506-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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

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 -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 id is 2205.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr1-186178506-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMCN1	NM_031935.3 linkuse as main transcript	c.16034A>G	p.Gln5345Arg	missense_variant	104/107	ENST00000271588.9	NP_114141.2	Q96RW7-1
HMCN1	XM_017002437.2 linkuse as main transcript	c.14057A>G	p.Gln4686Arg	missense_variant	93/96		XP_016857926.1
HMCN1	XM_047431608.1 linkuse as main transcript	c.11858A>G	p.Gln3953Arg	missense_variant	81/84		XP_047287564.1
HMCN1	XM_011510038.4 linkuse as main transcript	c.15944-3662A>G		intron_variant			XP_011508340.1	Q96RW7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9 linkuse as main transcript	c.16034A>G	p.Gln5345Arg	missense_variant	104/107	1	NM_031935.3	ENSP00000271588.4		Q96RW7-1
HMCN1	ENST00000414277.1 linkuse as main transcript	c.320-3662A>G		intron_variant		3		ENSP00000406205.1		Q5TCP6

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

GnomAD3 exomes

AF:

0.000733

AC:

184

AN:

250876

Hom.:

AF XY:

0.000819

AC XY:

111

AN XY:

135552

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 SAS 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

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00135

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152302

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00127

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

Uncertain significance, 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). 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

MACULAR DEGENERATION, AGE-RELATED, 1, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

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

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

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

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