rs8074840

Variant names:

• chr17-1771135-T-C
• rs8074840
• NM_002615.7:c.390T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002615.7(SERPINF1):​c.390T>C​(p.Thr130Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,613,536 control chromosomes in the GnomAD database, including 79,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6433 hom., cov: 31)
  • Exomes 𝑓: 0.31 (72859 hom.)
• Consequence: SERPINF1 NM_002615.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.16
• Publications: 40 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-1771135-T-C is Benign according to our data. Variant chr17-1771135-T-C is described in ClinVar as Benign. ClinVar VariationId is 322003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002615.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF1	NM_002615.7	MANE Select	c.390T>C	p.Thr130Thr	synonymous	Exon 4 of 8	NP_002606.3
	SERPINF1	NM_001329903.2		c.390T>C	p.Thr130Thr	synonymous	Exon 4 of 8	NP_001316832.1	A0A140VKF3
	SERPINF1	NM_001329904.2		c.-172T>C		5_prime_UTR	Exon 3 of 7	NP_001316833.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF1	ENST00000254722.9	TSL:1 MANE Select	c.390T>C	p.Thr130Thr	synonymous	Exon 4 of 8	ENSP00000254722.4	P36955
	SERPINF1	ENST00000869424.1		c.390T>C	p.Thr130Thr	synonymous	Exon 4 of 8	ENSP00000539483.1
	SERPINF1	ENST00000869426.1		c.390T>C	p.Thr130Thr	synonymous	Exon 4 of 8	ENSP00000539485.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42087 AN: 151804 Hom.: 6427 Cov.: 31

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.327 AC: 82109 AN: 251308 AF XY: 0.325

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.311 AC: 453879 AN: 1461614 Hom.: 72859 Cov.: 37 AF XY: 0.311 AC XY: 226406 AN XY: 727090

African (AFR) AF: 0.145 AC: 4846 AN: 33476

American (AMR) AF: 0.428 AC: 19125 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6119 AN: 26130

East Asian (EAS) AF: 0.412 AC: 16342 AN: 39692

South Asian (SAS) AF: 0.347 AC: 29919 AN: 86250

European-Finnish (FIN) AF: 0.396 AC: 21129 AN: 53398

Middle Eastern (MID) AF: 0.241 AC: 1392 AN: 5764

European-Non Finnish (NFE) AF: 0.303 AC: 337265 AN: 1111812

Other (OTH) AF: 0.294 AC: 17742 AN: 60380

GnomAD4 genome AF: 0.277 AC: 42106 AN: 151922 Hom.: 6433 Cov.: 31 AF XY: 0.283 AC XY: 21008 AN XY: 74240

African (AFR) AF: 0.155 AC: 6443 AN: 41470

American (AMR) AF: 0.347 AC: 5295 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 835 AN: 3468

East Asian (EAS) AF: 0.379 AC: 1951 AN: 5148

South Asian (SAS) AF: 0.355 AC: 1710 AN: 4812

European-Finnish (FIN) AF: 0.408 AC: 4293 AN: 10532

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.306 AC: 20776 AN: 67940

Other (OTH) AF: 0.249 AC: 524 AN: 2102

Alfa AF: 0.293 Hom.: 29355

Bravo AF: 0.267

Asia WGS AF: 0.383 AC: 1326 AN: 3478

EpiCase AF: 0.296

EpiControl AF: 0.288

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Osteogenesis imperfecta type 6 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.095
DANN	Benign	0.27
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs8074840; hg19: chr17-1674429; COSMIC: COSV54615256; COSMIC: COSV54615256;