7-107186631-A-G

Variant names:

• chr7-107186631-A-G
• rs767868646
• NM_012257.4:c.715A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_012257.4(HBP1):​c.715A>G​(p.Arg239Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HBP1 NM_012257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32026577).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBP1	NM_012257.4	c.715A>G	p.Arg239Gly	missense_variant	Exon 6 of 11	ENST00000222574.9	NP_036389.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBP1	ENST00000222574.9	c.715A>G	p.Arg239Gly	missense_variant	Exon 6 of 11	1	NM_012257.4	ENSP00000222574.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251344 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461036 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.715A>G (p.R239G) alteration is located in exon 6 (coding exon 5) of the HBP1 gene. This alteration results from a A to G substitution at nucleotide position 715, causing the arginine (R) at amino acid position 239 to be replaced by a glycine (G). 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	0.079
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Benign	-0.057
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.4	L;L;L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.44	N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.028	D;D;D;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.066	B;B;B;.
Vest4		0.60
MutPred		0.67		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP		0.99
MPC		0.045
ClinPred		0.083	T
GERP RS		3.5
Varity_R		0.22
gMVP		0.51

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: rs767868646; hg19: chr7-106827076;