chr1-185734629-C-A

Position:

• chr1-185734629-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031935.3(HMCN1):​c.-151C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 733,240 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: HMCN1 NM_031935.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.155

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BS2: High AC in GnomAd4 at 227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMCN1	NM_031935.3	c.-151C>A		5_prime_UTR_variant	1/107	ENST00000271588.9
HMCN1	XM_011510038.4	c.-151C>A		5_prime_UTR_variant	1/106
HMCN1	XM_011510041.4	c.-151C>A		5_prime_UTR_variant	1/61
HMCN1	XM_024450118.2	c.-151C>A		5_prime_UTR_variant	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMCN1	ENST00000271588.9	c.-151C>A		5_prime_UTR_variant	1/107	1	NM_031935.3	P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00168 AC: 977 AN: 580936 Hom.: 3 Cov.: 7 AF XY: 0.00162 AC XY: 504 AN XY: 312060

Gnomad4 AFR exome AF: 0.000434

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.0000584

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74474

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000319 Hom.: 0

Bravo AF: 0.00146

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Age related macular degeneration 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.9
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143020055; hg19: chr1-185703761;