chr17-48529875-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_002144.4(HOXB1):c.578C>G(p.Ala193Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,573,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HOXB1
NM_002144.4 missense, splice_region

Scores

Splicing: ADA: 0.00003228

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.527

Publications

0 publications found

Variant links:

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

HOXB1 links:

ENSG00000294508 (HGNC:):

ENSG00000294508 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0871321).

BP6

Variant 17-48529875-G-C is Benign according to our data. Variant chr17-48529875-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2516834.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB1	NM_002144.4 link	c.578C>G	p.Ala193Gly	missense_variant, splice_region_variant	Exon 2 of 2	ENST00000239174.7	NP_002135.2	P14653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HOXB1	ENST00000239174.7 link	c.578C>G	p.Ala193Gly	missense_variant, splice_region_variant	Exon 2 of 2	1	NM_002144.4	ENSP00000355140.5	P14653-1
HOXB1	ENST00000577092.1 link	c.*331C>G		3_prime_UTR_variant	Exon 1 of 1	6		ENSP00000459066.1	P14653-2
ENSG00000294508	ENST00000724000.1 link	n.817+1502G>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000132

AC:

AN:

227500

AF XY:

0.0000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000929

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000106

AC:

AN:

1421210

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

702964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32864

American (AMR)

AF:

0.00

AC:

AN:

43150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25122

East Asian (EAS)

AF:

0.00

AC:

AN:

39148

South Asian (SAS)

AF:

0.0000836

AC:

AN:

83684

European-Finnish (FIN)

AF:

0.0000258

AC:

AN:

38720

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1093862

Other (OTH)

AF:

0.0000508

AC:

AN:

59018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jun 12, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.055

T;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.62

.;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.087

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.53

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.54

N;.

REVEL

Benign

0.18

Sift

Benign

1.0

T;.

Sift4G

Benign

0.61

T;.

Polyphen

0.019

B;B

Vest4

0.058

MutPred

0.35

Loss of stability (P = 0.0383);Loss of stability (P = 0.0383);

MVP

0.69

MPC

0.43

ClinPred

0.031

GERP RS

2.8

Varity_R

0.093

gMVP

0.60

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.086

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

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chr17-48529875-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over