1-185734750-A-AG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_031935.3(HMCN1):c.-25dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,612,344 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (13 hom.)
• Consequence: HMCN1 NM_031935.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.496

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMCN1	NM_031935.3	c.-25dup		5_prime_UTR_variant	1/107	ENST00000271588.9
HMCN1	XM_011510038.4	c.-25dup		5_prime_UTR_variant	1/106
HMCN1	XM_011510041.4	c.-25dup		5_prime_UTR_variant	1/61
HMCN1	XM_024450118.2	c.-25dup		5_prime_UTR_variant	1/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMCN1	ENST00000271588.9	c.-25dup		5_prime_UTR_variant	1/107	1	NM_031935.3	P1

Frequencies

GnomAD3 genomes AF: 0.000474 AC: 72 AN: 152018 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00976

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00173 AC: 432 AN: 249974 Hom.: 3 AF XY: 0.00222 AC XY: 300 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000655

Gnomad SAS exome AF: 0.0120

Gnomad FIN exome AF: 0.000609

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000839 AC: 1225 AN: 1460208 Hom.: 13 Cov.: 30 AF XY: 0.00114 AC XY: 828 AN XY: 726530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.000567

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152136 Hom.: 2 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00976

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Macular degeneration Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs545770705; hg19: chr1-185703882;