7-107195896-G-A

Variant summary

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

The NM_012257.4(HBP1):c.1130G>A(p.Arg377His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HBP1 NM_012257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBP1	NM_012257.4	c.1130G>A	p.Arg377His	missense_variant	9/11	ENST00000222574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBP1	ENST00000222574.9	c.1130G>A	p.Arg377His	missense_variant	9/11	1	NM_012257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461302 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727016

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 02, 2021

The c.1130G>A (p.R377H) alteration is located in exon 9 (coding exon 8) of the HBP1 gene. This alteration results from a G to A substitution at nucleotide position 1130, causing the arginine (R) at amino acid position 377 to be replaced by a histidine (H). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.54
MutPred		0.47		Loss of MoRF binding (P = 0.0598);Loss of MoRF binding (P = 0.0598);Loss of MoRF binding (P = 0.0598);.;
MVP		0.88
MPC		2.1
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.74

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: chr7-106836341; COSMIC: COSV99753595; COSMIC: COSV99753595;