chr17-48529659-T-C

Position:

• chr17-48529659-T-C

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.794A>G​(p.Glu265Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,610,438 control chromosomes in the GnomAD database, including 801,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.99 (74118 hom., cov: 32)
  • Exomes 𝑓: 1.0 (727017 hom.)
• Consequence: HOXB1 NM_002144.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.09

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=5.513341E-7).
• BP6: Variant 17-48529659-T-C is Benign according to our data. Variant chr17-48529659-T-C is described in ClinVar as [Benign]. Clinvar id is 1175019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-48529659-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXB1	NM_002144.4	c.794A>G	p.Glu265Gly	missense_variant	2/2	ENST00000239174.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXB1	ENST00000239174.7	c.794A>G	p.Glu265Gly	missense_variant	2/2	1	NM_002144.4	P1
HOXB1	ENST00000577092.1	c.*547A>G		3_prime_UTR_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150115 AN: 152200 Hom.: 74065 Cov.: 32

Gnomad AFR AF: 0.952

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.988

GnomAD3 exomes AF: 0.996 AC: 250022 AN: 250964 Hom.: 124561 AF XY: 0.997 AC XY: 135272 AN XY: 135638

Gnomad AFR exome AF: 0.949

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1456033 AN: 1458120 Hom.: 727017 Cov.: 52 AF XY: 0.999 AC XY: 723670 AN XY: 724584

Gnomad4 AFR exome AF: 0.950

Gnomad4 AMR exome AF: 0.997

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.986 AC: 150227 AN: 152318 Hom.: 74118 Cov.: 32 AF XY: 0.987 AC XY: 73494 AN XY: 74480

Gnomad4 AFR AF: 0.952

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.988

Alfa AF: 0.997 Hom.: 116136

Bravo AF: 0.984

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.953 AC: 4198

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 0.996 AC: 120862

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

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

Facial paresis, hereditary congenital, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.029	.;T
MetaRNN	Benign	5.5e-7	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.0	N;N
MutationTaster	Benign	0.76	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	4.5	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.74	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;B
Vest4		0.029
MPC		0.50
ClinPred		0.0048	T
GERP RS		5.2
Varity_R		0.049
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: rs7226137; hg19: chr17-46607021; COSMIC: COSV53318074;