1-186132407-A-C

Position:

• chr1-186132407-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031935.3(HMCN1):​c.13310A>C​(p.Gln4437Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMCN1 NM_031935.3 missense, splice_region
• Scores: Splicing: ADA: 0.6881
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.50

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMCN1	NM_031935.3	c.13310A>C	p.Gln4437Pro	missense_variant, splice_region_variant	86/107	ENST00000271588.9	NP_114141.2
HMCN1	XM_011510038.4	c.13310A>C	p.Gln4437Pro	missense_variant, splice_region_variant	86/106		XP_011508340.1
HMCN1	XM_017002437.2	c.11333A>C	p.Gln3778Pro	missense_variant, splice_region_variant	75/96		XP_016857926.1
HMCN1	XM_047431608.1	c.9134A>C	p.Gln3045Pro	missense_variant, splice_region_variant	63/84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9	c.13310A>C	p.Gln4437Pro	missense_variant, splice_region_variant	86/107	1	NM_031935.3	ENSP00000271588	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	3.2e-8	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.50		Gain of glycosylation at Q4437 (P = 0.0254);
MVP		0.65
MPC		0.48
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.69
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: rs10911825; hg19: chr1-186101539;