17-1776708-T-C

Variant names:

• chr17-1776708-T-C
• rs6828
• NM_002615.7:c.963T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002615.7(SERPINF1):​c.963T>C​(p.Tyr321Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,612,732 control chromosomes in the GnomAD database, including 422,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45174 hom., cov: 25)
  • Exomes 𝑓: 0.72 (376985 hom.)
• Consequence: SERPINF1 NM_002615.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.70
• Publications: 32 publications found

Genes affected

SERPINF1 (HGNC:8824): (serpin family F member 1) This gene encodes a member of the serpin family that does not display the serine protease inhibitory activity shown by many of the other serpin proteins. The encoded protein is secreted and strongly inhibits angiogenesis. In addition, this protein is a neurotrophic factor involved in neuronal differentiation in retinoblastoma cells. Mutations in this gene were found in individuals with osteogenesis imperfecta, type VI. [provided by RefSeq, Aug 2016]

SERPINF1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 6

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000295186 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-1776708-T-C is Benign according to our data. Variant chr17-1776708-T-C is described in ClinVar as Benign. ClinVar VariationId is 322012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.963T>C	p.Tyr321Tyr	synonymous_variant	Exon 7 of 8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329903.2	c.963T>C	p.Tyr321Tyr	synonymous_variant	Exon 7 of 8		NP_001316832.1
SERPINF1	NM_001329904.2	c.402T>C	p.Tyr134Tyr	synonymous_variant	Exon 6 of 7		NP_001316833.1
SERPINF1	NM_001329905.2	c.402T>C	p.Tyr134Tyr	synonymous_variant	Exon 3 of 4		NP_001316834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.963T>C	p.Tyr321Tyr	synonymous_variant	Exon 7 of 8	1	NM_002615.7	ENSP00000254722.4

Frequencies

GnomAD3 genomes AF: 0.769 AC: 115930 AN: 150796 Hom.: 45118 Cov.: 25

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.739

GnomAD2 exomes AF: 0.732 AC: 184079 AN: 251460 AF XY: 0.722

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.794

Gnomad FIN exome AF: 0.736

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.716 AC: 1047273 AN: 1461818 Hom.: 376985 Cov.: 61 AF XY: 0.713 AC XY: 518171 AN XY: 727216

African (AFR) AF: 0.901 AC: 30152 AN: 33480

American (AMR) AF: 0.793 AC: 35468 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 18439 AN: 26134

East Asian (EAS) AF: 0.802 AC: 31824 AN: 39700

South Asian (SAS) AF: 0.635 AC: 54812 AN: 86256

European-Finnish (FIN) AF: 0.740 AC: 39546 AN: 53414

Middle Eastern (MID) AF: 0.657 AC: 3791 AN: 5768

European-Non Finnish (NFE) AF: 0.710 AC: 789953 AN: 1111950

Other (OTH) AF: 0.717 AC: 43288 AN: 60394

GnomAD4 genome AF: 0.769 AC: 116045 AN: 150914 Hom.: 45174 Cov.: 25 AF XY: 0.768 AC XY: 56499 AN XY: 73608

African (AFR) AF: 0.896 AC: 36889 AN: 41174

American (AMR) AF: 0.757 AC: 11419 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2476 AN: 3464

East Asian (EAS) AF: 0.787 AC: 3975 AN: 5048

South Asian (SAS) AF: 0.638 AC: 2977 AN: 4664

European-Finnish (FIN) AF: 0.737 AC: 7660 AN: 10394

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48212 AN: 67788

Other (OTH) AF: 0.737 AC: 1544 AN: 2096

Alfa AF: 0.735 Hom.: 33728

Bravo AF: 0.779

Asia WGS AF: 0.706 AC: 2455 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.701

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Osteogenesis imperfecta type 6 Benign:2

Medical Molecular Genetics Department, National Research Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Benign:1

Jun 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.026
DANN	Benign	0.60
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6828; hg19: chr17-1680002; COSMIC: COSV54615659; COSMIC: COSV54615659;