rs137853892

Variant names:

• chr11-75566582-T-C
• rs137853892
• NM_001235.5:c.233T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001235.5(SERPINH1):​c.233T>C​(p.Leu78Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L78L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SERPINH1 NM_001235.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.93
• Publications: 14 publications found

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]

SERPINH1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 10

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-75566582-T-C is Pathogenic according to our data. Variant chr11-75566582-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30141.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001235.5. 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
	SERPINH1	NM_001235.5	MANE Select	c.233T>C	p.Leu78Pro	missense	Exon 2 of 5	NP_001226.2
	SERPINH1	NM_001207014.3		c.233T>C	p.Leu78Pro	missense	Exon 3 of 6	NP_001193943.1	P50454
	SERPINH1	NM_001440311.1		c.233T>C	p.Leu78Pro	missense	Exon 3 of 6	NP_001427240.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINH1	ENST00000358171.8	TSL:1 MANE Select	c.233T>C	p.Leu78Pro	missense	Exon 2 of 5	ENSP00000350894.4	P50454
	SERPINH1	ENST00000530284.5	TSL:1	c.233T>C	p.Leu78Pro	missense	Exon 3 of 5	ENSP00000436305.1	E9PPV6
	SERPINH1	ENST00000524558.5	TSL:2	c.233T>C	p.Leu78Pro	missense	Exon 2 of 5	ENSP00000434412.1	P50454

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Osteogenesis imperfecta type 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of stability (P = 0.0166)
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.99
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs137853892; hg19: chr11-75277627;