17-1776708-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002615.7(SERPINF1):c.963T>C(p.Tyr321=) 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:4
• Conservation: PhyloP100: -3.70

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 322012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1776708-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.963T>C	p.Tyr321=	synonymous_variant	7/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.963T>C	p.Tyr321=	synonymous_variant	7/8
SERPINF1	NM_001329904.2	c.402T>C	p.Tyr134=	synonymous_variant	6/7
SERPINF1	NM_001329905.2	c.402T>C	p.Tyr134=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.963T>C	p.Tyr321=	synonymous_variant	7/8	1	NM_002615.7	P1
SERPINF1	ENST00000573763.1	c.357T>C	p.Tyr119=	synonymous_variant	3/4	3
SERPINF1	ENST00000572517.1	n.259T>C		non_coding_transcript_exon_variant	1/2	2

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

GnomAD3 exomes AF: 0.732 AC: 184079 AN: 251460 Hom.: 68037 AF XY: 0.722 AC XY: 98169 AN XY: 135906

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 SAS exome AF: 0.634

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

Gnomad4 AFR exome AF: 0.901

Gnomad4 AMR exome AF: 0.793

Gnomad4 ASJ exome AF: 0.706

Gnomad4 EAS exome AF: 0.802

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.740

Gnomad4 NFE exome AF: 0.710

Gnomad4 OTH exome AF: 0.717

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

Gnomad4 AFR AF: 0.896

Gnomad4 AMR AF: 0.757

Gnomad4 ASJ AF: 0.715

Gnomad4 EAS AF: 0.787

Gnomad4 SAS AF: 0.638

Gnomad4 FIN AF: 0.737

Gnomad4 NFE AF: 0.711

Gnomad4 OTH AF: 0.737

Alfa AF: 0.735 Hom.: 30529

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Medical Molecular Genetics Department, National Research Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2017

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.026
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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