rs41317471

Positions:

• chr1-186007238-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_031935.3(HMCN1):​c.4586A>G​(p.Asn1529Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00727 in 1,613,750 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (51 hom.)
• Consequence: HMCN1 NM_031935.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 6.87

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012983948).
• BP6: Variant 1-186007238-A-G is Benign according to our data. Variant chr1-186007238-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 96207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-186007238-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 818 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMCN1	NM_031935.3	c.4586A>G	p.Asn1529Ser	missense_variant	30/107	ENST00000271588.9	NP_114141.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9	c.4586A>G	p.Asn1529Ser	missense_variant	30/107	1	NM_031935.3	ENSP00000271588	P1

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 818 AN: 152178 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00590 AC: 1480 AN: 251036 Hom.: 9 AF XY: 0.00594 AC XY: 806 AN XY: 135664

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00886

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00747 AC: 10918 AN: 1461454 Hom.: 51 Cov.: 30 AF XY: 0.00733 AC XY: 5328 AN XY: 727050

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00247

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.00847

Gnomad4 OTH exome AF: 0.00750

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152296 Hom.: 2 Cov.: 32 AF XY: 0.00523 AC XY: 389 AN XY: 74446

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00894

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00735 Hom.: 4

Bravo AF: 0.00448

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00581 AC: 706

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00699

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 23, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.55
Sift	Benign	0.24	T
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.63
MVP		0.89
MPC		0.071
ClinPred		0.028	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.71

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

Other links and lift over

dbSNP: rs41317471; hg19: chr1-185976370;