17-1769810-G-A

Variant names:

• chr17-1769810-G-A
• rs11658342
• NM_002615.7:c.85-42G>A

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.85-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,606,138 control chromosomes in the GnomAD database, including 100,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7040 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93593 hom.)
• Consequence: SERPINF1 NM_002615.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.209
• Publications: 27 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=-0.81).
• BP6: Variant 17-1769810-G-A is Benign according to our data. Variant chr17-1769810-G-A is described in ClinVar as Benign. ClinVar VariationId is 674942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.85-42G>A		intron_variant	Intron 2 of 7	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329903.2	c.85-42G>A		intron_variant	Intron 2 of 7		NP_001316832.1
SERPINF1	NM_001329904.2	c.-477-42G>A		intron_variant	Intron 1 of 6		NP_001316833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.85-42G>A		intron_variant	Intron 2 of 7	1	NM_002615.7	ENSP00000254722.4

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43112 AN: 152028 Hom.: 7044 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.304 AC: 76044 AN: 250022 AF XY: 0.313

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.352 AC: 512221 AN: 1453992 Hom.: 93593 Cov.: 28 AF XY: 0.350 AC XY: 253623 AN XY: 723814

African (AFR) AF: 0.134 AC: 4474 AN: 33318

American (AMR) AF: 0.186 AC: 8305 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9012 AN: 26100

East Asian (EAS) AF: 0.233 AC: 9247 AN: 39660

South Asian (SAS) AF: 0.254 AC: 21842 AN: 86118

European-Finnish (FIN) AF: 0.325 AC: 17283 AN: 53198

Middle Eastern (MID) AF: 0.337 AC: 1934 AN: 5744

European-Non Finnish (NFE) AF: 0.380 AC: 419700 AN: 1105018

Other (OTH) AF: 0.340 AC: 20424 AN: 60124

GnomAD4 genome AF: 0.283 AC: 43110 AN: 152146 Hom.: 7040 Cov.: 33 AF XY: 0.281 AC XY: 20887 AN XY: 74396

African (AFR) AF: 0.139 AC: 5760 AN: 41518

American (AMR) AF: 0.235 AC: 3591 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3472

East Asian (EAS) AF: 0.276 AC: 1427 AN: 5178

South Asian (SAS) AF: 0.239 AC: 1154 AN: 4822

European-Finnish (FIN) AF: 0.310 AC: 3274 AN: 10576

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.374 AC: 25456 AN: 67980

Other (OTH) AF: 0.308 AC: 650 AN: 2108

Alfa AF: 0.336 Hom.: 28397

Bravo AF: 0.273

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.60
PhyloP100		-0.21
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: rs11658342; hg19: chr17-1673104; COSMIC: COSV54616140; COSMIC: COSV54616140;