7-107185925-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_012257.4(HBP1):c.523C>T(p.Pro175Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,612,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: HBP1 NM_012257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.180

Genes affected

HBP1 (HGNC:23200): (HMG-box transcription factor 1) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of lipid transport; negative regulation of reactive oxygen species biosynthetic process; and negative regulation of transcription by RNA polymerase II. Located in nuclear speck. Biomarker of osteoarthritis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02685219).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBP1	NM_012257.4	c.523C>T	p.Pro175Ser	missense_variant	4/11	ENST00000222574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBP1	ENST00000222574.9	c.523C>T	p.Pro175Ser	missense_variant	4/11	1	NM_012257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251240 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000107 AC: 157 AN: 1460502 Hom.: 1 Cov.: 29 AF XY: 0.000102 AC XY: 74 AN XY: 726616

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.523C>T (p.P175S) alteration is located in exon 4 (coding exon 3) of the HBP1 gene. This alteration results from a C to T substitution at nucleotide position 523, causing the proline (P) at amino acid position 175 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.34	N;N;N;.
MutationTaster	Benign	0.82	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.043	D;D;D;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.099
MVP		0.20
MPC		0.038
ClinPred		0.036	T
GERP RS		2.9
Varity_R		0.039
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs780296098; hg19: chr7-106826370; COSMIC: COSV56018292; COSMIC: COSV56018292;