chr19-3576912-C-A

Variant names:

• chr19-3576912-C-A
• rs2032173695
• NM_006339.3:c.613C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006339.3(HMG20B):​c.613C>A​(p.Arg205Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HMG20B NM_006339.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

Genes affected

HMG20B (HGNC:5002): (high mobility group 20B) Predicted to enable DNA binding activity. Predicted to be involved in regulation of gene expression. Predicted to act upstream of or within negative regulation of protein sumoylation; positive regulation of neuron differentiation; and skeletal muscle cell differentiation. Located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMG20B	NM_006339.3	c.613C>A	p.Arg205Ser	missense_variant	Exon 8 of 10	ENST00000333651.11	NP_006330.2
HMG20B	XM_017026144.2	c.610C>A	p.Arg204Ser	missense_variant	Exon 8 of 10		XP_016881633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMG20B	ENST00000333651.11	c.613C>A	p.Arg205Ser	missense_variant	Exon 8 of 10	1	NM_006339.3	ENSP00000328269.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424276 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 705230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.613C>A (p.R205S) alteration is located in exon 8 (coding exon 7) of the HMG20B gene. This alteration results from a C to A substitution at nucleotide position 613, causing the arginine (R) at amino acid position 205 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;T;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.1	.;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;D;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.012	D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.94	.;P;.;.
Vest4		0.61
MutPred		0.24		Gain of phosphorylation at R205 (P = 0.0226);Gain of phosphorylation at R205 (P = 0.0226);.;.;
MVP		0.87
MPC		2.0
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.70

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: rs2032173695; hg19: chr19-3576910;