chr17-44148179-A-C

Position:

• chr17-44148179-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001171251.3(HROB):​c.376A>C​(p.Thr126Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,906 control chromosomes in the GnomAD database, including 112,733 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (21461 hom., cov: 32)
  • Exomes 𝑓: 0.33 (91272 hom.)
• Consequence: HROB NM_001171251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126

Genes affected

HROB (HGNC:28460): (homologous recombination factor with OB-fold) Predicted to enable single-stranded DNA binding activity. Involved in DNA synthesis involved in DNA repair and interstrand cross-link repair. Located in site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1212045E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HROB	NM_001171251.3	c.376A>C	p.Thr126Pro	missense_variant	3/10	ENST00000585683.6	NP_001164722.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HROB	ENST00000585683.6	c.376A>C	p.Thr126Pro	missense_variant	3/10	2	NM_001171251.3	ENSP00000466618	A2
HROB	ENST00000319977.8	c.376A>C	p.Thr126Pro	missense_variant	3/10	1		ENSP00000313500	P4
HROB	ENST00000245382.6	c.376A>C	p.Thr126Pro	missense_variant	3/7	1		ENSP00000245382
HROB	ENST00000588434.1	n.409A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72975 AN: 151902 Hom.: 21401 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.435

GnomAD3 exomes AF: 0.401 AC: 100882 AN: 251326 Hom.: 24259 AF XY: 0.381 AC XY: 51735 AN XY: 135854

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.787

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.334 AC: 488486 AN: 1461886 Hom.: 91272 Cov.: 60 AF XY: 0.331 AC XY: 240596 AN XY: 727246

Gnomad4 AFR exome AF: 0.830

Gnomad4 AMR exome AF: 0.456

Gnomad4 ASJ exome AF: 0.482

Gnomad4 EAS exome AF: 0.744

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.320

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.481 AC: 73099 AN: 152020 Hom.: 21461 Cov.: 32 AF XY: 0.479 AC XY: 35624 AN XY: 74298

Gnomad4 AFR AF: 0.814

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.776

Gnomad4 SAS AF: 0.307

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.434

Alfa AF: 0.355 Hom.: 23716

Bravo AF: 0.513

TwinsUK AF: 0.293 AC: 1085

ALSPAC AF: 0.285 AC: 1099

ESP6500AA AF: 0.794 AC: 3497

ESP6500EA AF: 0.310 AC: 2666

ExAC AF: 0.402 AC: 48809

Asia WGS AF: 0.533 AC: 1856 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.3
DANN	Benign	0.10
DEOGEN2	Benign	0.0015	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.14	T;T;T
MetaRNN	Benign	0.0000011	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.8	N;N;N
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	2.2	N;.;N
REVEL	Benign	0.070
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.033
MPC		0.16
ClinPred		0.0019	T
GERP RS		1.5
Varity_R		0.050
gMVP		0.051

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: rs227584; hg19: chr17-42225547; COSMIC: COSV55370618;