11-75566449-G-A

Variant summary

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

The NM_001235.5(SERPINH1):c.100G>A(p.Glu34Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E34E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINH1 NM_001235.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

Genes affected

SERPINH1 (HGNC:1546): (serpin family H member 1) This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The encoded protein is localized to the endoplasmic reticulum and plays a role in collagen biosynthesis as a collagen-specific molecular chaperone. Autoantibodies to the encoded protein have been found in patients with rheumatoid arthritis. Expression of this gene may be a marker for cancer, and nucleotide polymorphisms in this gene may be associated with preterm birth caused by preterm premature rupture of membranes. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, May 2011]

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=0.21976775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINH1	NM_001235.5	c.100G>A	p.Glu34Lys	missense_variant	2/5	ENST00000358171.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINH1	ENST00000358171.8	c.100G>A	p.Glu34Lys	missense_variant	2/5	1	NM_001235.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459948 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Invitae

Nov 05, 2021

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINH1 protein function. This variant has not been reported in the literature in individuals affected with SERPINH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 34 of the SERPINH1 protein (p.Glu34Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.41	T;T;.;.;T;T;T;T;.;.;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.75	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N;N;.;.;.;.;.;N;.;.;.;.
MutationTaster	Benign	0.68	N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.28	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.50	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;B;.;B;.;.;.;.
Vest4		0.32
MutPred		0.37		Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);
MVP		0.81
MPC		0.26
ClinPred		0.28	T
GERP RS		4.8
Varity_R		0.098
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-75277494;