19-3574384-C-G

Variant names:

• chr19-3574384-C-G
• NM_006339.3:c.149C>G

Variant summary

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

The NM_006339.3(HMG20B):​c.149C>G​(p.Pro50Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000209 in 1,432,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMG20B NM_006339.3 missense, splice_region
• Scores: Splicing: ADA: 0.02814
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

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]

MFSD12 (HGNC:28299): (major facilitator superfamily domain containing 12) Enables cysteine transmembrane transporter activity. Involved in cysteine transmembrane transport; pigment metabolic process involved in pigmentation; and regulation of melanin biosynthetic process. Located in lysosome and melanosome. Part of late endosome. [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.149C>G	p.Pro50Arg	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000333651.11	NP_006330.2
HMG20B	XM_017026144.2	c.149C>G	p.Pro50Arg	missense_variant, splice_region_variant	Exon 4 of 10		XP_016881633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMG20B	ENST00000333651.11	c.149C>G	p.Pro50Arg	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_006339.3	ENSP00000328269.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1432008 Hom.: 0 Cov.: 34 AF XY: 0.00000282 AC XY: 2 AN XY: 709708

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: 0.00000182

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149C>G (p.P50R) alteration is located in exon 4 (coding exon 3) of the HMG20B gene. This alteration results from a C to G substitution at nucleotide position 149, causing the proline (P) at amino acid position 50 to be replaced by an arginine (R). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T;T;.
Eigen	Benign	0.055
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.53	T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.54	D;D;T;D
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.81	.;P;.;.
Vest4		0.42
MutPred		0.23		Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);.;Gain of MoRF binding (P = 0.0025);
MVP		0.99
MPC		1.7
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.18
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.028
dbscSNV1_RF	Benign	0.36
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-3574382;