11-57598295-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000062.3(SERPING1):c.25A>C(p.Thr9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,562,280 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.901

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01342231).
• BP6: Variant 11-57598295-A-C is Benign according to our data. Variant chr11-57598295-A-C is described in ClinVar as [Benign]. Clinvar id is 1167822.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57598295-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00144 (217/151070) while in subpopulation AFR AF= 0.00495 (203/41012). AF 95% confidence interval is 0.00439. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.25A>C	p.Thr9Pro	missense_variant	2/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.25A>C	p.Thr9Pro	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.25A>C	p.Thr9Pro	missense_variant	2/8	1	NM_000062.3	P2

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 217 AN: 150952 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000355 AC: 60 AN: 168948 Hom.: 0 AF XY: 0.000264 AC XY: 24 AN XY: 90884

Gnomad AFR exome AF: 0.00489

Gnomad AMR exome AF: 0.000454

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000186 AC: 263 AN: 1411210 Hom.: 2 Cov.: 32 AF XY: 0.000184 AC XY: 128 AN XY: 697428

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.000586

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000552

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00144 AC: 217 AN: 151070 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 113 AN XY: 73762

Gnomad4 AFR AF: 0.00495

Gnomad4 AMR AF: 0.000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.00159

ESP6500AA AF: 0.00232 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000179 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.050	T;T;T;.;.;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.43	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N;D;N;N;N;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Uncertain	0.036	D;D;D;D;D;D;D
Polyphen		0.99, 1.0	.;D;.;.;.;D;.
Vest4		0.38, 0.39, 0.38, 0.21, 0.29
MVP		0.82
MPC		0.72
ClinPred		0.042	T
GERP RS		2.6
Varity_R		0.40
gMVP		0.71

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: rs201455616; hg19: chr11-57365768;