17-1769982-C-T

Variant names:

• chr17-1769982-C-T
• rs1136287
• NM_002615.7:c.215C>T

Variant summary

Our verdict is Benign. The variant received -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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.215C>T	p.Thr72Met	missense_variant	Exon 3 of 8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329904.2	c.-347C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7		NP_001316833.1
SERPINF1	NM_001329903.2	c.215C>T	p.Thr72Met	missense_variant	Exon 3 of 8		NP_001316832.1
SERPINF1	NM_001329904.2	c.-347C>T		5_prime_UTR_variant	Exon 2 of 7		NP_001316833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.215C>T	p.Thr72Met	missense_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.609 AC: 153242 AN: 251434 AF XY: 0.606

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 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 AC: 28385 AN: 33480

Gnomad4 AMR exome AF: 0.527 AC: 23582 AN: 44724

Gnomad4 ASJ exome AF: 0.725 AC: 18949 AN: 26136

Gnomad4 EAS exome AF: 0.495 AC: 19665 AN: 39698

Gnomad4 SAS exome AF: 0.492 AC: 42459 AN: 86258

Gnomad4 FIN exome AF: 0.560 AC: 29910 AN: 53406

Gnomad4 NFE exome AF: 0.643 AC: 714626 AN: 1111870

Gnomad4 Remaining exome AF: 0.644 AC: 38897 AN: 60388

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 AC: 0.834811 AN: 0.834811

Gnomad4 AMR AF: 0.607 AC: 0.606928 AN: 0.606928

Gnomad4 ASJ AF: 0.721 AC: 0.720749 AN: 0.720749

Gnomad4 EAS AF: 0.522 AC: 0.522278 AN: 0.522278

Gnomad4 SAS AF: 0.480 AC: 0.480449 AN: 0.480449

Gnomad4 FIN AF: 0.550 AC: 0.550199 AN: 0.550199

Gnomad4 NFE AF: 0.643 AC: 0.642828 AN: 0.642828

Gnomad4 OTH AF: 0.703 AC: 0.703406 AN: 0.703406

Alfa AF: 0.657 Hom.: 168674

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

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 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. -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta type 6 Benign:3

Mar 06, 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. -

-

Medical Molecular Genetics Department, National Research Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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

Publications

LitVar

Other links and lift over

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