17-48530596-T-A

Variant names:

• chr17-48530596-T-A
• rs12939811
• NM_002144.4:c.309A>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 37 publications found

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]

HOXB1 Gene-Disease associations (from GenCC):

• facial paresis, hereditary congenital, 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• congenital hereditary facial paralysis-variable hearing loss syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294508 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
HOXB1	NM_002144.4	c.309A>T	p.Gln103His	missense_variant	Exon 1 of 2	ENST00000239174.7	NP_002135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXB1	ENST00000239174.7	c.309A>T	p.Gln103His	missense_variant	Exon 1 of 2	1	NM_002144.4	ENSP00000355140.5
HOXB1	ENST00000577092.1	c.309A>T	p.Gln103His	missense_variant	Exon 1 of 1	6		ENSP00000459066.1
ENSG00000294508	ENST00000724000.1	n.817+2223T>A		intron_variant	Intron 2 of 2

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

GnomAD2 exomes AF: 0.161 AC: 40355 AN: 250544 AF XY: 0.163

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 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

African (AFR) AF: 0.0718 AC: 2403 AN: 33478

American (AMR) AF: 0.113 AC: 5048 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5057 AN: 26134

East Asian (EAS) AF: 0.0575 AC: 2284 AN: 39700

South Asian (SAS) AF: 0.124 AC: 10706 AN: 86256

European-Finnish (FIN) AF: 0.221 AC: 11796 AN: 53306

Middle Eastern (MID) AF: 0.142 AC: 818 AN: 5768

European-Non Finnish (NFE) AF: 0.196 AC: 217531 AN: 1111962

Other (OTH) AF: 0.174 AC: 10525 AN: 60392

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

African (AFR) AF: 0.0749 AC: 3114 AN: 41560

American (AMR) AF: 0.135 AC: 2068 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3472

East Asian (EAS) AF: 0.0878 AC: 452 AN: 5150

South Asian (SAS) AF: 0.132 AC: 640 AN: 4832

European-Finnish (FIN) AF: 0.223 AC: 2367 AN: 10602

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13320 AN: 67972

Other (OTH) AF: 0.163 AC: 343 AN: 2106

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-1.4
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
PromoterAI		-0.0078	Neutral
Varity_R		0.13
gMVP		0.48
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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