17-1774962-G-A

Variant names:

• chr17-1774962-G-A
• rs2269344
• NM_002615.7:c.644-96G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002615.7(SERPINF1):​c.644-96G>A variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINF1 NM_002615.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.97
• Publications: 12 publications found

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]

SERPINF1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 6

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002615.7. 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
	SERPINF1	NM_002615.7	MANE Select	c.644-96G>A		intron	N/A	NP_002606.3
	SERPINF1	NM_001329903.2		c.644-96G>A		intron	N/A	NP_001316832.1	A0A140VKF3
	SERPINF1	NM_001329904.2		c.83-96G>A		intron	N/A	NP_001316833.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF1	ENST00000254722.9	TSL:1 MANE Select	c.644-96G>A		intron	N/A	ENSP00000254722.4	P36955
	SERPINF1	ENST00000869424.1		c.644-96G>A		intron	N/A	ENSP00000539483.1
	SERPINF1	ENST00000869426.1		c.644-96G>A		intron	N/A	ENSP00000539485.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.31e-7 AC: 1 AN: 1367966 Hom.: 0 AF XY: 0.00000146 AC XY: 1 AN XY: 685206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31366

American (AMR) AF: 0.00 AC: 0 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 39160

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4968

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1031294

Other (OTH) AF: 0.00 AC: 0 AN: 57290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0070
DANN	Benign	0.87
PhyloP100		-5.0

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: rs2269344; hg19: chr17-1678256;