chr17-48530596-T-A

Position:

• chr17-48530596-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002144.4(HOXB1):​c.309A>T​(p.Gln103His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,613,906 control chromosomes in the GnomAD database, including 27,379 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2043 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25336 hom.)
• Consequence: HOXB1 NM_002144.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.43

Genes affected

HOXB1 (HGNC:5111): (homeobox B1) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXB genes located in a cluster on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011953115).
• BP6: Variant 17-48530596-T-A is Benign according to our data. Variant chr17-48530596-T-A is described in ClinVar as [Benign]. Clinvar id is 1239766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-48530596-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXB1	NM_002144.4	c.309A>T	p.Gln103His	missense_variant	1/2	ENST00000239174.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXB1	ENST00000239174.7	c.309A>T	p.Gln103His	missense_variant	1/2	1	NM_002144.4	P1
HOXB1	ENST00000577092.1	c.309A>T	p.Gln103His	missense_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23256 AN: 152076 Hom.: 2042 Cov.: 32

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.161 AC: 40355 AN: 250544 Hom.: 3617 AF XY: 0.163 AC XY: 22128 AN XY: 135592

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.0889

Gnomad SAS exome AF: 0.123

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.182 AC: 266168 AN: 1461712 Hom.: 25336 Cov.: 33 AF XY: 0.181 AC XY: 131342 AN XY: 727164

Gnomad4 AFR exome AF: 0.0718

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.0575

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.153 AC: 23258 AN: 152194 Hom.: 2043 Cov.: 32 AF XY: 0.153 AC XY: 11384 AN XY: 74400

Gnomad4 AFR AF: 0.0749

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.0878

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.163

Alfa AF: 0.171 Hom.: 1858

Bravo AF: 0.142

TwinsUK AF: 0.203 AC: 751

ALSPAC AF: 0.187 AC: 721

ESP6500AA AF: 0.0778 AC: 343

ESP6500EA AF: 0.188 AC: 1621

ExAC AF: 0.161 AC: 19528

Asia WGS AF: 0.131 AC: 455 AN: 3478

EpiCase AF: 0.195

EpiControl AF: 0.194

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.4
DANN	Benign	0.83
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.45	.;T;T
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.015	D;.;.
Sift4G	Benign	0.077	T;.;D
Polyphen		0.64	P;P;.
Vest4		0.26
MutPred		0.10		Gain of catalytic residue at Q103 (P = 0.0787);Gain of catalytic residue at Q103 (P = 0.0787);Gain of catalytic residue at Q103 (P = 0.0787);
MPC		0.71
ClinPred		0.030	T
GERP RS		-5.7
Varity_R		0.13
gMVP		0.48

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: rs12939811; hg19: chr17-46607958; COSMIC: COSV53316862;