21-39345208-C-T

Variant names:

• chr21-39345208-C-T
• rs1419058815
• NM_004965.7:c.193G>A

Variant summary

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

The NM_004965.7(HMGN1):​c.193G>A​(p.Val65Met) 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 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HMGN1 NM_004965.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

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 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=0.17501423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGN1	NM_004965.7	c.193G>A	p.Val65Met	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.193G>A	p.Val65Met	missense_variant	Exon 5 of 6	1	NM_004965.7	ENSP00000370125.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461506 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193G>A (p.V65M) 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 193, causing the valine (V) at amino acid position 65 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	0.034
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.014	B;.;.
Vest4		0.28
MutPred		0.33		Gain of helix (P = 0.0854);.;.;
MVP		0.20
MPC		0.033
ClinPred		0.56	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.019

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: rs1419058815; hg19: chr21-40717134;