22-35283958-T-C

Variant names:

• chr22-35283958-T-C
• rs2272789
• NM_001003681.3:c.1216-4T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001003681.3(HMGXB4):​c.1216-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,608,806 control chromosomes in the GnomAD database, including 362,462 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (27605 hom., cov: 34)
  • Exomes 𝑓: 0.67 (334857 hom.)
• Consequence: HMGXB4 NM_001003681.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001029
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.892
• Publications: 22 publications found

Genes affected

HMGXB4 (HGNC:5003): (HMG-box containing 4) High mobility group (HMG) proteins are nonhistone chromosomal proteins. See HMG2 (MIM 163906) for additional information on HMG proteins.[supplied by OMIM, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGXB4	NM_001003681.3	c.1216-4T>C		splice_region_variant, intron_variant	Intron 5 of 10	ENST00000216106.6	NP_001003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGXB4	ENST00000216106.6	c.1216-4T>C		splice_region_variant, intron_variant	Intron 5 of 10	5	NM_001003681.3	ENSP00000216106.5
HMGXB4	ENST00000418170.5	n.*1052-4T>C		splice_region_variant, intron_variant	Intron 6 of 11	1		ENSP00000395532.1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88668 AN: 152044 Hom.: 27612 Cov.: 34

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.708

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.637 AC: 159932 AN: 251250 AF XY: 0.643

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.614

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.674 AC: 982288 AN: 1456644 Hom.: 334857 Cov.: 31 AF XY: 0.674 AC XY: 488249 AN XY: 724932

African (AFR) AF: 0.333 AC: 11118 AN: 33404

American (AMR) AF: 0.586 AC: 26169 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 18336 AN: 26106

East Asian (EAS) AF: 0.604 AC: 23944 AN: 39654

South Asian (SAS) AF: 0.609 AC: 52401 AN: 86108

European-Finnish (FIN) AF: 0.642 AC: 34299 AN: 53402

Middle Eastern (MID) AF: 0.611 AC: 3517 AN: 5756

European-Non Finnish (NFE) AF: 0.698 AC: 772409 AN: 1107298

Other (OTH) AF: 0.666 AC: 40095 AN: 60234

GnomAD4 genome AF: 0.583 AC: 88687 AN: 152162 Hom.: 27605 Cov.: 34 AF XY: 0.580 AC XY: 43184 AN XY: 74408

African (AFR) AF: 0.352 AC: 14601 AN: 41512

American (AMR) AF: 0.591 AC: 9035 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 2458 AN: 3472

East Asian (EAS) AF: 0.617 AC: 3203 AN: 5188

South Asian (SAS) AF: 0.611 AC: 2947 AN: 4826

European-Finnish (FIN) AF: 0.653 AC: 6908 AN: 10584

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.697 AC: 47406 AN: 67982

Other (OTH) AF: 0.633 AC: 1332 AN: 2104

Alfa AF: 0.650 Hom.: 29190

Bravo AF: 0.569

Asia WGS AF: 0.602 AC: 2096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=65/35	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.014
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: rs2272789; hg19: chr22-35679951; COSMIC: COSV53335374; COSMIC: COSV53335374;