17-1766939-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_002615.7(SERPINF1):c.29T>C(p.Ile10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,565,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I10N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SERPINF1
NM_002615.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.725

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.075324655).

BP6

Variant 17-1766939-T-C is Benign according to our data. Variant chr17-1766939-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1397364.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SERPINF1	NM_002615.7 linkuse as main transcript	c.29T>C	p.Ile10Thr	missense_variant	2/8	ENST00000254722.9
SERPINF1	NM_001329903.2 linkuse as main transcript	c.29T>C	p.Ile10Thr	missense_variant	2/8
SERPINF1	NM_001329904.2 linkuse as main transcript	c.-477-2913T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9 linkuse as main transcript	c.29T>C	p.Ile10Thr	missense_variant	2/8	1	NM_002615.7	P1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000568

AC:

AN:

175920

Hom.:

AF XY:

0.0000107

AC XY:

AN XY:

93680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1413362

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

698520

show subpopulations

Gnomad4 AFR exome

AF:

0.0000927

Gnomad4 AMR exome

AF:

0.0000267

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000120

Gnomad4 OTH exome

AF:

0.0000342

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000831

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 10 of the SERPINF1 protein (p.Ile10Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SERPINF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1397364). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.0055

BayesDel_noAF

Benign

-0.25

Cadd

Benign

7.0

Dann

Benign

0.61

DEOGEN2

Benign

0.055

T;T;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.55

T;T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.075

T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-2.5

N;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.72

N;.;.;.;.

REVEL

Benign

0.20

Sift

Benign

0.38

T;.;.;.;.

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.0

B;.;.;.;.

Vest4

0.19

MutPred

0.67

Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);

MVP

0.51

MPC

0.082

ClinPred

0.037

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over