rs3891224

Variant names:

• chr17-1775044-A-T
• rs3891224
• NM_002615.7:c.644-14A>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.644-14A>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.06
• Publications: 10 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=-0.87).
• BP6: Variant 17-1775044-A-T is Benign according to our data. Variant chr17-1775044-A-T is described in ClinVar as Benign. ClinVar VariationId is 322008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.644-14A>T		intron_variant	Intron 5 of 7	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329903.2	c.644-14A>T		intron_variant	Intron 5 of 7		NP_001316832.1
SERPINF1	NM_001329904.2	c.83-14A>T		intron_variant	Intron 4 of 6		NP_001316833.1
SERPINF1	NM_001329905.2	c.83-14A>T		intron_variant	Intron 1 of 3		NP_001316834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.644-14A>T		intron_variant	Intron 5 of 7	1	NM_002615.7	ENSP00000254722.4
SERPINF1	ENST00000573763.1	c.43-19A>T		intron_variant	Intron 1 of 3	3		ENSP00000461405.1
SERPINF1	ENST00000572048.1	c.83-14A>T		intron_variant	Intron 1 of 2	2		ENSP00000458484.1
SERPINF1	ENST00000576406.5	c.83-14A>T		intron_variant	Intron 4 of 5	3		ENSP00000461214.1

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

GnomAD2 exomes AF: 0.0842 AC: 21162 AN: 251386 AF XY: 0.0760

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 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

African (AFR) AF: 0.316 AC: 10576 AN: 33458

American (AMR) AF: 0.161 AC: 7222 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3773 AN: 26134

East Asian (EAS) AF: 0.160 AC: 6353 AN: 39696

South Asian (SAS) AF: 0.0643 AC: 5546 AN: 86250

European-Finnish (FIN) AF: 0.0206 AC: 1100 AN: 53420

Middle Eastern (MID) AF: 0.0715 AC: 412 AN: 5766

European-Non Finnish (NFE) AF: 0.0321 AC: 35688 AN: 1111888

Other (OTH) AF: 0.0676 AC: 4083 AN: 60380

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

African (AFR) AF: 0.306 AC: 12656 AN: 41406

American (AMR) AF: 0.137 AC: 2096 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3472

East Asian (EAS) AF: 0.130 AC: 672 AN: 5168

South Asian (SAS) AF: 0.0750 AC: 362 AN: 4828

European-Finnish (FIN) AF: 0.0208 AC: 220 AN: 10602

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0348 AC: 2368 AN: 68022

Other (OTH) AF: 0.126 AC: 267 AN: 2112

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Sep 13, 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. -

Osteogenesis imperfecta type 6 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.19
DANN	Benign	0.57
PhyloP100		-1.1
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: rs3891224; hg19: chr17-1678338; COSMIC: COSV54616279; COSMIC: COSV54616279;