1-185734829-A-T

Variant names:

• chr1-185734829-A-T
• rs375537965
• NM_031935.3:c.50A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031935.3(HMCN1):​c.50A>T​(p.Tyr17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMCN1 NM_031935.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.142
• Publications: 1 publications found

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]

HMCN1 Gene-Disease associations (from GenCC):

• age related macular degeneration 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042458266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031935.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMCN1	NM_031935.3	MANE Select	c.50A>T	p.Tyr17Phe	missense	Exon 1 of 107	NP_114141.2	Q96RW7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMCN1	ENST00000271588.9	TSL:1 MANE Select	c.50A>T	p.Tyr17Phe	missense	Exon 1 of 107	ENSP00000271588.4	Q96RW7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.3
DANN	Benign	0.86
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.14
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.056
Sift	Benign	0.52	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.35		Loss of catalytic residue at L12 (P = 0.1286)
MVP		0.17
MPC		0.075
ClinPred		0.027	T
GERP RS		-2.3
PromoterAI		0.12	Neutral
Varity_R		0.074
gMVP		0.24
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375537965; hg19: chr1-185703961;