17-35764307-T-C

Variant names:

• chr17-35764307-T-C
• rs782385657
• NM_145272.4:c.314T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145272.4(C17orf50):​c.314T>C​(p.Leu105Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,494,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: C17orf50 NM_145272.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

C17orf50 (HGNC:29581): (chromosome 17 open reading frame 50)

MMP28 (HGNC:14366): (matrix metallopeptidase 28) Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix for both normal physiological processes, such as embryonic development, reproduction and tissue remodeling, and disease processes, such as asthma and metastasis. This gene encodes a secreted enzyme that degrades casein. Its expression pattern suggests that it plays a role in tissue homeostasis and in wound repair. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09594777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C17orf50	NM_145272.4	c.314T>C	p.Leu105Pro	missense_variant	Exon 2 of 3	ENST00000605587.2	NP_660315.2
MMP28	XM_011525231.2	c.1168+3445A>G		intron_variant	Intron 7 of 7		XP_011523533.1
MMP28	XM_017025064.2	c.*27+3445A>G		intron_variant	Intron 7 of 7		XP_016880553.1
MMP28	NR_111988.2	n.2100+1890A>G		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C17orf50	ENST00000605587.2	c.314T>C	p.Leu105Pro	missense_variant	Exon 2 of 3	1	NM_145272.4	ENSP00000475146.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151862 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000202 AC: 19 AN: 94264 Hom.: 0 AF XY: 0.000232 AC XY: 12 AN XY: 51666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000518

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000215 AC: 289 AN: 1342916 Hom.: 0 Cov.: 31 AF XY: 0.000209 AC XY: 138 AN XY: 658930

Gnomad4 AFR exome AF: 0.0000711

Gnomad4 AMR exome AF: 0.000104

Gnomad4 ASJ exome AF: 0.000358

Gnomad4 EAS exome AF: 0.0000297

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000433

Gnomad4 NFE exome AF: 0.000231

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151862 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74182

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000292 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314T>C (p.L105P) alteration is located in exon 2 (coding exon 2) of the C17orf50 gene. This alteration results from a T to C substitution at nucleotide position 314, causing the leucine (L) at amino acid position 105 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
Sift4G	Pathogenic	0.0	D
Polyphen		0.56	P
Vest4		0.32
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0104);
MVP		0.27
ClinPred		0.057	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.064

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: rs782385657; hg19: chr17-34091326;