rs3891224

chr17-1775044-A-T

Variant summary

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

The NM_002615.7(SERPINF1):c.644-14A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,613,784 control chromosomes in the GnomAD database, including 6,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2253 hom., cov: 31)
  • Exomes 𝑓: 0.051 (4283 hom.)
• Consequence: SERPINF1 NM_002615.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-1775044-A-T is Benign according to our data. Variant chr17-1775044-A-T is described in ClinVar as [Benign]. Clinvar id is 322008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1775044-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.644-14A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000254722.9
SERPINF1	NM_001329903.2	c.644-14A>T		splice_polypyrimidine_tract_variant, intron_variant
SERPINF1	NM_001329904.2	c.83-14A>T		splice_polypyrimidine_tract_variant, intron_variant
SERPINF1	NM_001329905.2	c.83-14A>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.644-14A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002615.7	P1
SERPINF1	ENST00000572048.1	c.83-14A>T		splice_polypyrimidine_tract_variant, intron_variant		2
SERPINF1	ENST00000573763.1	c.43-19A>T		intron_variant		3
SERPINF1	ENST00000576406.5	c.83-14A>T		splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19105 AN: 151954 Hom.: 2242 Cov.: 31

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0753

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0842 AC: 21162 AN: 251386 Hom.: 1705 AF XY: 0.0760 AC XY: 10323 AN XY: 135860

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.0632

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0698

GnomAD4 exome AF: 0.0511 AC: 74753 AN: 1461712 Hom.: 4283 Cov.: 34 AF XY: 0.0506 AC XY: 36803 AN XY: 727170

Gnomad4 AFR exome AF: 0.316

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.0643

Gnomad4 FIN exome AF: 0.0206

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0676

GnomAD4 genome AF: 0.126 AC: 19151 AN: 152072 Hom.: 2253 Cov.: 31 AF XY: 0.125 AC XY: 9282 AN XY: 74348

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.0750

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.126

Alfa AF: 0.0853 Hom.: 201

Bravo AF: 0.144

Asia WGS AF: 0.109 AC: 379 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 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

- -

Osteogenesis imperfecta type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.19
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3891224; hg19: chr17-1678338; COSMIC: COSV54616279; COSMIC: COSV54616279;