rs646474

Variant names:

• chr11-75568402-T-C
• rs646474
• NM_001235.5:c.623-329T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001235.5(SERPINH1):​c.623-329T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 410,126 control chromosomes in the GnomAD database, including 45,139 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (14298 hom., cov: 31)
  • Exomes 𝑓: 0.47 (30841 hom.)
• Consequence: SERPINH1 NM_001235.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331
• Publications: 6 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, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINH1	NM_001235.5	c.623-329T>C		intron_variant	Intron 2 of 4	ENST00000358171.8	NP_001226.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINH1	ENST00000358171.8	c.623-329T>C		intron_variant	Intron 2 of 4	1	NM_001235.5	ENSP00000350894.4

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60609 AN: 151926 Hom.: 14299 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.456

GnomAD4 exome AF: 0.473 AC: 121992 AN: 258082 Hom.: 30841 Cov.: 0 AF XY: 0.462 AC XY: 63919 AN XY: 138220

African (AFR) AF: 0.150 AC: 1134 AN: 7538

American (AMR) AF: 0.350 AC: 4502 AN: 12866

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 3542 AN: 7144

East Asian (EAS) AF: 0.265 AC: 3551 AN: 13388

South Asian (SAS) AF: 0.348 AC: 14365 AN: 41328

European-Finnish (FIN) AF: 0.446 AC: 5466 AN: 12252

Middle Eastern (MID) AF: 0.488 AC: 500 AN: 1024

European-Non Finnish (NFE) AF: 0.554 AC: 82426 AN: 148764

Other (OTH) AF: 0.472 AC: 6506 AN: 13778

GnomAD4 genome AF: 0.399 AC: 60598 AN: 152044 Hom.: 14298 Cov.: 31 AF XY: 0.391 AC XY: 29038 AN XY: 74312

African (AFR) AF: 0.155 AC: 6426 AN: 41508

American (AMR) AF: 0.381 AC: 5810 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1717 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1404 AN: 5168

South Asian (SAS) AF: 0.342 AC: 1647 AN: 4816

European-Finnish (FIN) AF: 0.429 AC: 4527 AN: 10544

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37544 AN: 67950

Other (OTH) AF: 0.452 AC: 955 AN: 2114

Alfa AF: 0.480 Hom.: 10168

Bravo AF: 0.386

Asia WGS AF: 0.271 AC: 943 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.74
PhyloP100		0.33
Mutation Taster		=300/0	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: rs646474; hg19: chr11-75279447;