chrX-81115177-A-T

Variant names:

• chrX-81115177-A-T
• rs1183434045
• NM_030763.3:c.321T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030763.3(HMGN5):​c.321T>A​(p.Asp107Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,060,115 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: HMGN5 NM_030763.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.319

Genes affected

HMGN5 (HGNC:8013): (high mobility group nucleosome binding domain 5) This gene encodes a nuclear protein with similarities to the high mobility group proteins, HMG14 and HMG17, which suggests that this protein may function as a nucleosomal binding and transcriptional activating protein. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09313026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGN5	NM_030763.3	c.321T>A	p.Asp107Glu	missense_variant	Exon 7 of 7	ENST00000358130.7	NP_110390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGN5	ENST00000358130.7	c.321T>A	p.Asp107Glu	missense_variant	Exon 7 of 7	2	NM_030763.3	ENSP00000350848.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000377 AC: 4 AN: 1060115 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 1 AN XY: 338913

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: 0.00000485

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.321T>A (p.D107E) alteration is located in exon 7 (coding exon 6) of the HMGN5 gene. This alteration results from a T to A substitution at nucleotide position 321, causing the aspartic acid (D) at amino acid position 107 to be replaced by a glutamic acid (E). 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	Benign	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.0
DANN	Benign	0.81
DEOGEN2	Benign	0.014	T;T;.;.
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.38	T;T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;D;N;N
REVEL	Benign	0.082
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.99	D;.;.;.
Vest4		0.063
MutPred		0.24		Gain of methylation at K111 (P = 0.1464);.;.;Gain of methylation at K111 (P = 0.1464);
MVP		0.44
MPC		0.019
ClinPred		0.12	T
GERP RS		2.6
Varity_R		0.20
gMVP		0.0025

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: rs1183434045; hg19: chrX-80370676;