17-1766925-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6 BP7 BS1

The NM_002615.7(SERPINF1):c.15G>T(p.Val5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000927 in 1,563,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: SERPINF1 NM_002615.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.10

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-1766925-G-T is Benign according to our data. Variant chr17-1766925-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 890646.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=3.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000637 (97/152300) while in subpopulation SAS AF= 0.00145 (7/4824). AF 95% confidence interval is 0.000942. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.15G>T	p.Val5=	synonymous_variant	2/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.15G>T	p.Val5=	synonymous_variant	2/8
SERPINF1	NM_001329904.2	c.-477-2927G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.15G>T	p.Val5=	synonymous_variant	2/8	1	NM_002615.7	P1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000573 AC: 99 AN: 172744 Hom.: 0 AF XY: 0.000643 AC XY: 59 AN XY: 91828

Gnomad AFR exome AF: 0.0000994

Gnomad AMR exome AF: 0.0000764

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000978

Gnomad OTH exome AF: 0.000216

GnomAD4 exome AF: 0.000959 AC: 1353 AN: 1411090 Hom.: 1 Cov.: 31 AF XY: 0.00106 AC XY: 740 AN XY: 697218

Gnomad4 AFR exome AF: 0.000155

Gnomad4 AMR exome AF: 0.0000808

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000804

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74470

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.000514

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Osteogenesis imperfecta Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 17, 2022

- -

Osteogenesis imperfecta type 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	2.5
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs139841572; hg19: chr17-1670219; COSMIC: COSV99629066; COSMIC: COSV99629066;