17-1766972-A-C

Position:

• chr17-1766972-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002615.7(SERPINF1):​c.62A>C​(p.Asn21Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINF1 NM_002615.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11232743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.62A>C	p.Asn21Thr	missense_variant	2/8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329903.2	c.62A>C	p.Asn21Thr	missense_variant	2/8		NP_001316832.1
SERPINF1	NM_001329904.2	c.-477-2880A>C		intron_variant			NP_001316833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.62A>C	p.Asn21Thr	missense_variant	2/8	1	NM_002615.7	ENSP00000254722	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1353798). This variant has not been reported in the literature in individuals affected with SERPINF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine with threonine at codon 21 of the SERPINF1 protein (p.Asn21Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.068	T;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.52	T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.99	N;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.069	T;.;.;.;.
Sift4G	Benign	0.42	T;D;D;D;D
Polyphen		0.041	B;.;.;.;.
Vest4		0.44
MutPred		0.25		Gain of glycosylation at N21 (P = 0.0051);Gain of glycosylation at N21 (P = 0.0051);Gain of glycosylation at N21 (P = 0.0051);Gain of glycosylation at N21 (P = 0.0051);Gain of glycosylation at N21 (P = 0.0051);
MVP		0.79
MPC		0.077
ClinPred		0.089	T
GERP RS		2.3
Varity_R		0.10
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1907422119; hg19: chr17-1670266;