5-177280796-C-G

Variant names:

• chr5-177280796-C-G
• NM_022455.5:c.5854C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_022455.5(NSD1):​c.5854C>G​(p.Arg1952Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1952W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59

Genes affected

NSD1 (HGNC:14234): (nuclear receptor binding SET domain protein 1) This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgen receptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutations of this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocation with the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd on chromosome 11. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Sep 2018]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain SET (size 117) in uniprot entity NSD1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_022455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177280796-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the NSD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 153 curated benign missense variants. Gene score misZ: 3.4113 (above the threshold of 3.09). Trascript score misZ: 5.7368 (above the threshold of 3.09). GenCC associations: The gene is linked to Beckwith-Wiedemann syndrome, Weaver syndrome, Sotos syndrome 1, Sotos syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.5854C>G	p.Arg1952Gly	missense_variant	Exon 18 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.5854C>G	p.Arg1952Gly	missense_variant	Exon 18 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.9	.;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.041	D;D;D
Polyphen		1.0	D;P;D
Vest4		0.76
MutPred		0.71		.;Loss of MoRF binding (P = 0.0096);.;
MVP		0.99
MPC		2.6
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -25

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: chr5-176707797;