chr21-39345211-C-T

Variant names:

• chr21-39345211-C-T
• rs139139360
• NM_004965.7:c.190G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004965.7(HMGN1):​c.190G>A​(p.Glu64Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,613,594 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: HMGN1 NM_004965.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

Genes affected

HMGN1 (HGNC:4984): (high mobility group nucleosome binding domain 1) The protein encoded by this gene binds nucleosomal DNA and is associated with transcriptionally active chromatin. Along with a similar protein, HMG17, the encoded protein may help maintain an open chromatin configuration around transcribable genes. [provided by RefSeq, Aug 2011]

LOC124905074 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09216756).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGN1	NM_004965.7	c.190G>A	p.Glu64Lys	missense_variant	Exon 5 of 6	ENST00000380749.10	NP_004956.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGN1	ENST00000380749.10	c.190G>A	p.Glu64Lys	missense_variant	Exon 5 of 6	1	NM_004965.7	ENSP00000370125.5

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152008 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000410 AC: 103 AN: 251146 Hom.: 1 AF XY: 0.000457 AC XY: 62 AN XY: 135790

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000342 AC: 500 AN: 1461468 Hom.: 2 Cov.: 33 AF XY: 0.000363 AC XY: 264 AN XY: 727040

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000320

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000343 Hom.: 1

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000654

EpiControl AF: 0.000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190G>A (p.E64K) alteration is located in exon 5 (coding exon 5) of the HMGN1 gene. This alteration results from a G to A substitution at nucleotide position 190, causing the glutamic acid (E) at amino acid position 64 to be replaced by a lysine (K). 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	0.23
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T;T;T
Eigen	Benign	-0.055
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T;T;D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.62
MVP		0.43
MPC		0.0067
ClinPred		0.045	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.047

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: rs139139360; hg19: chr21-40717137;