rs1136287

Variant names:

• chr17-1769982-C-T
• rs1136287
• NM_002615.7:c.215C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-1769982-C-T
• chr17-1769982-C-G

Variant summary

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

The NM_001329904.2(SERPINF1):​c.-347C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,816 control chromosomes in the GnomAD database, including 329,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36046 hom., cov: 32)
  • Exomes 𝑓: 0.63 (293400 hom.)
• Consequence: SERPINF1 NM_001329904.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.725
• Publications: 112 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7483504E-6).
• BP6: Variant 17-1769982-C-T is Benign according to our data. Variant chr17-1769982-C-T is described in ClinVar as Benign. ClinVar VariationId is 322000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329904.2. 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.215C>T	p.Thr72Met	missense	Exon 3 of 8	NP_002606.3
	SERPINF1	NM_001329904.2		c.-347C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001316833.1
	SERPINF1	NM_001329903.2		c.215C>T	p.Thr72Met	missense	Exon 3 of 8	NP_001316832.1	A0A140VKF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF1	ENST00000254722.9	TSL:1 MANE Select	c.215C>T	p.Thr72Met	missense	Exon 3 of 8	ENSP00000254722.4	P36955
	SERPINF1	ENST00000576406.5	TSL:3	c.-347C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000461214.1	I3L4F9
	SERPINF1	ENST00000869424.1		c.215C>T	p.Thr72Met	missense	Exon 3 of 8	ENSP00000539483.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103173 AN: 151970 Hom.: 35998 Cov.: 32

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.609 AC: 153242 AN: 251434 AF XY: 0.606

Gnomad AFR exome AF: 0.837

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.723

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.649

Gnomad OTH exome AF: 0.631

GnomAD4 exome AF: 0.630 AC: 920378 AN: 1461726 Hom.: 293400 Cov.: 74 AF XY: 0.625 AC XY: 454704 AN XY: 727170

African (AFR) AF: 0.848 AC: 28385 AN: 33480

American (AMR) AF: 0.527 AC: 23582 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 18949 AN: 26136

East Asian (EAS) AF: 0.495 AC: 19665 AN: 39698

South Asian (SAS) AF: 0.492 AC: 42459 AN: 86258

European-Finnish (FIN) AF: 0.560 AC: 29910 AN: 53406

Middle Eastern (MID) AF: 0.677 AC: 3905 AN: 5766

European-Non Finnish (NFE) AF: 0.643 AC: 714626 AN: 1111870

Other (OTH) AF: 0.644 AC: 38897 AN: 60388

GnomAD4 genome AF: 0.679 AC: 103276 AN: 152090 Hom.: 36046 Cov.: 32 AF XY: 0.671 AC XY: 49891 AN XY: 74334

African (AFR) AF: 0.835 AC: 34653 AN: 41510

American (AMR) AF: 0.607 AC: 9269 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2501 AN: 3470

East Asian (EAS) AF: 0.522 AC: 2696 AN: 5162

South Asian (SAS) AF: 0.480 AC: 2310 AN: 4808

European-Finnish (FIN) AF: 0.550 AC: 5820 AN: 10578

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43693 AN: 67970

Other (OTH) AF: 0.703 AC: 1487 AN: 2114

Alfa AF: 0.657 Hom.: 168674

Bravo AF: 0.694

TwinsUK AF: 0.645 AC: 2393

ALSPAC AF: 0.655 AC: 2525

ESP6500AA AF: 0.829 AC: 3652

ESP6500EA AF: 0.652 AC: 5606

ExAC AF: 0.619 AC: 75103

Asia WGS AF: 0.498 AC: 1737 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.659

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Osteogenesis imperfecta type 6 (3)
-	-	2	not provided (2)
-	-	1	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.2
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.084	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.72
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.28
Sift	Benign	0.27	T
Sift4G	Benign	0.19	T
Polyphen		0.0050	B
Vest4		0.080
MPC		0.072
ClinPred		0.029	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.30
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: rs1136287; hg19: chr17-1673276; COSMIC: COSV54616828; COSMIC: COSV54616828;