NM_001304504.2:c.555C>G

Variant names:

• chr15-77471014-C-G
• NM_001304504.2:c.555C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001304504.2(HMG20A):​c.555C>G​(p.Asp185Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMG20A NM_001304504.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

HMG20A (HGNC:5001): (high mobility group 20A) Enables identical protein binding activity. Predicted to be involved in regulation of gene expression. Predicted to act upstream of or within negative regulation of neuron differentiation; negative regulation of protein sumoylation; and negative regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000294779 (HGNC:):

ACMG classification

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=0.052888036).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304504.2. 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
	HMG20A	NM_001304504.2	MANE Select	c.555C>G	p.Asp185Glu	missense	Exon 5 of 10	NP_001291433.1	Q9NP66-1
	HMG20A	NM_018200.4		c.555C>G	p.Asp185Glu	missense	Exon 6 of 11	NP_060670.1	Q9NP66-1
	HMG20A	NM_001304505.2		c.216C>G	p.Asp72Glu	missense	Exon 5 of 10	NP_001291434.1	B4DMG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMG20A	ENST00000336216.9	TSL:1 MANE Select	c.555C>G	p.Asp185Glu	missense	Exon 5 of 10	ENSP00000336856.4	Q9NP66-1
	HMG20A	ENST00000381714.7	TSL:1	c.555C>G	p.Asp185Glu	missense	Exon 6 of 11	ENSP00000371133.3	Q9NP66-1
	HMG20A	ENST00000859564.1		c.555C>G	p.Asp185Glu	missense	Exon 5 of 10	ENSP00000529622.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726252

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

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 44160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111380

Other (OTH) AF: 0.0000166 AC: 1 AN: 60292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.50
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.93	N
PhyloP100		2.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.12		Gain of methylation at K182 (P = 0.1553)
MVP		0.46
MPC		0.41
ClinPred		0.25	T
GERP RS		5.0
Varity_R		0.068
gMVP		0.056
Mutation Taster		=85/15	polymorphism

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

hg19: chr15-77763356;