chr22-35264882-G-T

Variant names:

• chr22-35264882-G-T
• rs1053593
• NM_001003681.3:c.494G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001003681.3(HMGXB4):​c.494G>T​(p.Gly165Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,613,482 control chromosomes in the GnomAD database, including 313,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (22276 hom., cov: 31)
  • Exomes 𝑓: 0.62 (290932 hom.)
• Consequence: HMGXB4 NM_001003681.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.34
• Publications: 55 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.2052422E-6).
• BP6: Variant 22-35264882-G-T is Benign according to our data. Variant chr22-35264882-G-T is described in ClinVar as [Benign]. Clinvar id is 1235870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGXB4	NM_001003681.3	c.494G>T	p.Gly165Val	missense_variant	Exon 5 of 11	ENST00000216106.6	NP_001003681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGXB4	ENST00000216106.6	c.494G>T	p.Gly165Val	missense_variant	Exon 5 of 11	5	NM_001003681.3	ENSP00000216106.5

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75542 AN: 151826 Hom.: 22292 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.570

GnomAD2 exomes AF: 0.585 AC: 146960 AN: 251232 AF XY: 0.594

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.538

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.651

Gnomad OTH exome AF: 0.620

GnomAD4 exome AF: 0.625 AC: 913117 AN: 1461538 Hom.: 290932 Cov.: 49 AF XY: 0.625 AC XY: 454348 AN XY: 727070

African (AFR) AF: 0.136 AC: 4545 AN: 33470

American (AMR) AF: 0.564 AC: 25209 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 17917 AN: 26132

East Asian (EAS) AF: 0.525 AC: 20859 AN: 39696

South Asian (SAS) AF: 0.570 AC: 49157 AN: 86236

European-Finnish (FIN) AF: 0.598 AC: 31950 AN: 53398

Middle Eastern (MID) AF: 0.589 AC: 3400 AN: 5768

European-Non Finnish (NFE) AF: 0.651 AC: 723277 AN: 1111736

Other (OTH) AF: 0.609 AC: 36803 AN: 60388

GnomAD4 genome AF: 0.497 AC: 75518 AN: 151944 Hom.: 22276 Cov.: 31 AF XY: 0.497 AC XY: 36882 AN XY: 74244

African (AFR) AF: 0.157 AC: 6514 AN: 41440

American (AMR) AF: 0.557 AC: 8501 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2388 AN: 3466

East Asian (EAS) AF: 0.539 AC: 2783 AN: 5168

South Asian (SAS) AF: 0.568 AC: 2734 AN: 4812

European-Finnish (FIN) AF: 0.606 AC: 6392 AN: 10544

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44217 AN: 67924

Other (OTH) AF: 0.569 AC: 1201 AN: 2112

Alfa AF: 0.608 Hom.: 130869

Bravo AF: 0.482

TwinsUK AF: 0.654 AC: 2425

ALSPAC AF: 0.655 AC: 2523

ESP6500AA AF: 0.165 AC: 728

ESP6500EA AF: 0.655 AC: 5637

ExAC AF: 0.578 AC: 70120

Asia WGS AF: 0.532 AC: 1852 AN: 3478

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

- -

Apr 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30389748) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.059	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.0000062	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	.;.;N
PhyloP100		1.3
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	D;D;N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.061	T;T;D
Polyphen		0.012	.;.;B
Vest4		0.18
MPC		0.18
ClinPred		0.018	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.11
Mutation Taster		=100/0	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: rs1053593; hg19: chr22-35660875; COSMIC: COSV53335269; COSMIC: COSV53335269;