NM_002615.7:c.440-39C>T

Variant names:

• chr17-1771833-C-T
• rs4274474
• NM_002615.7:c.440-39C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002615.7(SERPINF1):​c.440-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,592,992 control chromosomes in the GnomAD database, including 411,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43479 hom., cov: 31)
  • Exomes 𝑓: 0.71 (367667 hom.)
• Consequence: SERPINF1 NM_002615.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.89
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 6

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-1771833-C-T is Benign according to our data. Variant chr17-1771833-C-T is described in ClinVar as Benign. ClinVar VariationId is 674943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.440-39C>T		intron_variant	Intron 4 of 7	ENST00000254722.9	NP_002606.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.440-39C>T		intron_variant	Intron 4 of 7	1	NM_002615.7	ENSP00000254722.4

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114475 AN: 151998 Hom.: 43432 Cov.: 31

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.727

GnomAD2 exomes AF: 0.726 AC: 174475 AN: 240396 AF XY: 0.717

Gnomad AFR exome AF: 0.845

Gnomad AMR exome AF: 0.788

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.793

Gnomad FIN exome AF: 0.742

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.699

GnomAD4 exome AF: 0.713 AC: 1027090 AN: 1440876 Hom.: 367667 Cov.: 26 AF XY: 0.709 AC XY: 508871 AN XY: 717548

African (AFR) AF: 0.852 AC: 28297 AN: 33204

American (AMR) AF: 0.786 AC: 34981 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 18390 AN: 26024

East Asian (EAS) AF: 0.807 AC: 31937 AN: 39588

South Asian (SAS) AF: 0.631 AC: 54058 AN: 85650

European-Finnish (FIN) AF: 0.745 AC: 33969 AN: 45626

Middle Eastern (MID) AF: 0.644 AC: 2691 AN: 4180

European-Non Finnish (NFE) AF: 0.708 AC: 780328 AN: 1102338

Other (OTH) AF: 0.710 AC: 42439 AN: 59786

GnomAD4 genome AF: 0.753 AC: 114580 AN: 152116 Hom.: 43479 Cov.: 31 AF XY: 0.752 AC XY: 55959 AN XY: 74372

African (AFR) AF: 0.845 AC: 35077 AN: 41504

American (AMR) AF: 0.749 AC: 11452 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2484 AN: 3470

East Asian (EAS) AF: 0.786 AC: 4060 AN: 5166

South Asian (SAS) AF: 0.635 AC: 3065 AN: 4824

European-Finnish (FIN) AF: 0.738 AC: 7809 AN: 10586

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48214 AN: 67968

Other (OTH) AF: 0.725 AC: 1529 AN: 2110

Alfa AF: 0.720 Hom.: 48002

Bravo AF: 0.761

Asia WGS AF: 0.705 AC: 2450 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

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. -

Osteogenesis imperfecta type 6 Benign:1

-

Medical Molecular Genetics Department, National Research Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.67
PhyloP100		-2.9
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

Other links and lift over

dbSNP: rs4274474; hg19: chr17-1675127; COSMIC: COSV54616777; COSMIC: COSV54616777;