rs28932181

Variant names:

• chr5-177212104-T-A
• rs28932181
• NM_022455.5:c.3705T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-177212104-T-A
• chr5-177212104-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_022455.5(NSD1):​c.3705T>A​(p.Asn1235Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1235N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.158

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17799434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.3705T>A	p.Asn1235Lys	missense_variant	Exon 5 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.3705T>A	p.Asn1235Lys	missense_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.00066	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T;T;.
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.33	B;B;B
Vest4		0.18
MutPred		0.21		.;Gain of ubiquitination at N1235 (P = 0.0048);.;
MVP		0.70
MPC		0.061
ClinPred		0.76	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.17
gMVP		0.19

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: rs28932181; hg19: chr5-176639105;