17-1769982-C-T

Position:

• chr17-1769982-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001329904.2(SERPINF1):​c.-347C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,816 control chromosomes in the GnomAD database, including 329,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36046 hom., cov: 32)
  • Exomes 𝑓: 0.63 (293400 hom.)
• Consequence: SERPINF1 NM_001329904.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.725

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7483504E-6).
• BP6: Variant 17-1769982-C-T is Benign according to our data. Variant chr17-1769982-C-T is described in ClinVar as [Benign]. Clinvar id is 322000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1769982-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.215C>T	p.Thr72Met	missense_variant	3/8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329904.2	c.-347C>T		5_prime_UTR_premature_start_codon_gain_variant	2/7		NP_001316833.1
SERPINF1	NM_001329903.2	c.215C>T	p.Thr72Met	missense_variant	3/8		NP_001316832.1
SERPINF1	NM_001329904.2	c.-347C>T		5_prime_UTR_variant	2/7		NP_001316833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.215C>T	p.Thr72Met	missense_variant	3/8	1	NM_002615.7	ENSP00000254722.4

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103173 AN: 151970 Hom.: 35998 Cov.: 32

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.702

GnomAD3 exomes AF: 0.609 AC: 153242 AN: 251434 Hom.: 48150 AF XY: 0.606 AC XY: 82331 AN XY: 135904

Gnomad AFR exome AF: 0.837

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.723

Gnomad EAS exome AF: 0.543

Gnomad SAS exome AF: 0.489

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.649

Gnomad OTH exome AF: 0.631

GnomAD4 exome AF: 0.630 AC: 920378 AN: 1461726 Hom.: 293400 Cov.: 74 AF XY: 0.625 AC XY: 454704 AN XY: 727170

Gnomad4 AFR exome AF: 0.848

Gnomad4 AMR exome AF: 0.527

Gnomad4 ASJ exome AF: 0.725

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.560

Gnomad4 NFE exome AF: 0.643

Gnomad4 OTH exome AF: 0.644

GnomAD4 genome AF: 0.679 AC: 103276 AN: 152090 Hom.: 36046 Cov.: 32 AF XY: 0.671 AC XY: 49891 AN XY: 74334

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.721

Gnomad4 EAS AF: 0.522

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.703

Alfa AF: 0.653 Hom.: 84464

Bravo AF: 0.694

TwinsUK AF: 0.645 AC: 2393

ALSPAC AF: 0.655 AC: 2525

ESP6500AA AF: 0.829 AC: 3652

ESP6500EA AF: 0.652 AC: 5606

ExAC AF: 0.619 AC: 75103

Asia WGS AF: 0.498 AC: 1737 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.659

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Osteogenesis imperfecta type 6 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.2
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T;T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.084	T;T;T;T;T
MetaRNN	Benign	0.0000017	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L;.;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.50	N;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.27	T;.;.;.;.
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.0050	B;.;.;.;.
Vest4		0.080
MPC		0.072
ClinPred		0.029	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.30

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: rs1136287; hg19: chr17-1673276; COSMIC: COSV54616828; COSMIC: COSV54616828;