1-185734836-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_031935.3(HMCN1):c.57C>T(p.Ser19=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,613,930 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (57 hom.)
• Consequence: HMCN1 NM_031935.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.600

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 1-185734836-C-T is Benign according to our data. Variant chr1-185734836-C-T is described in ClinVar as [Benign]. Clinvar id is 294095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMCN1	NM_031935.3	c.57C>T	p.Ser19=	synonymous_variant	1/107	ENST00000271588.9
HMCN1	XM_011510038.4	c.57C>T	p.Ser19=	synonymous_variant	1/106
HMCN1	XM_024450118.2	c.57C>T	p.Ser19=	synonymous_variant	1/67
HMCN1	XM_011510041.4	c.57C>T	p.Ser19=	synonymous_variant	1/61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMCN1	ENST00000271588.9	c.57C>T	p.Ser19=	synonymous_variant	1/107	1	NM_031935.3	P1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2373 AN: 152068 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00544 AC: 1369 AN: 251496 Hom.: 22 AF XY: 0.00484 AC XY: 658 AN XY: 135922

Gnomad AFR exome AF: 0.0522

Gnomad AMR exome AF: 0.00549

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00256 AC: 3737 AN: 1461744 Hom.: 57 Cov.: 31 AF XY: 0.00256 AC XY: 1865 AN XY: 727206

Gnomad4 AFR exome AF: 0.0526

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00430

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000771

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.0157 AC: 2389 AN: 152186 Hom.: 71 Cov.: 32 AF XY: 0.0153 AC XY: 1138 AN XY: 74404

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00863 Hom.: 9

Bravo AF: 0.0183

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Age related macular degeneration 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	6.6
Dann	Benign	0.89

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: rs114170176; hg19: chr1-185703968;