19-3577039-C-A

Variant names:

• chr19-3577039-C-A
• rs1046228927
• NM_006339.3:c.740C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006339.3(HMG20B):​c.740C>A​(p.Ala247Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A247G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: HMG20B NM_006339.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30032146).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006339.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMG20B	NM_006339.3	MANE Select	c.740C>A	p.Ala247Glu	missense	Exon 8 of 10	NP_006330.2	Q9P0W2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMG20B	ENST00000333651.11	TSL:1 MANE Select	c.740C>A	p.Ala247Glu	missense	Exon 8 of 10	ENSP00000328269.6	Q9P0W2-1
	HMG20B	ENST00000488973.6	TSL:1	n.1653C>A		non_coding_transcript_exon	Exon 6 of 8
	HMG20B	ENST00000888792.1		c.740C>A	p.Ala247Glu	missense	Exon 8 of 10	ENSP00000558851.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396810 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689116

African (AFR) AF: 0.00 AC: 0 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 35828

South Asian (SAS) AF: 0.00 AC: 0 AN: 79202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4500

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079522

Other (OTH) AF: 0.00 AC: 0 AN: 57868

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.60	T
Polyphen		0.27	B
Vest4		0.53
MutPred		0.31		Loss of helix (P = 0.028)
MVP		0.68
MPC		2.0
ClinPred		0.89	D
GERP RS		4.0
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.85
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1046228927; hg19: chr19-3577037;