5-177135173-G-T

Variant names:

• chr5-177135173-G-T
• NM_022455.5:c.70G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_022455.5(NSD1):​c.70G>T​(p.Ala24Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.78

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 5 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.
• PP5: Variant 5-177135173-G-T is Pathogenic according to our data. Variant chr5-177135173-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3341084.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.70G>T	p.Ala24Ser	missense_variant	Exon 2 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.70G>T	p.Ala24Ser	missense_variant	Exon 2 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sotos syndrome Pathogenic:1

Aug 19, 2023

Faculty of Engineering and Natural Sciences, Biruni University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

With the c.70G>T missense change in NSD1 (NM_022455.5) gene, start loss occurs in the transcribed protein(PM5).Whether a missense or a splice site variant, computational prediction tools unanimously support a deleterious effect on the gene(PP3).There are no reports of this change in the gnomAD database, indicating that it is very low as a population frequency(PM2). It is expected to result in an disrupted protein product. Tatton-Brown et al. (2005) reviewed the clinical phenotype of 239 individuals with NSD1 abnormalities and found that facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of individuals; however, both height and head circumference were within the normal range in 10% of individuals, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome (PMID: 15942875).In the patient in whom mental retardation and seizure findings were observed together with global growth retardation, it was thought that Sotos syndrome was formed with the c.70G>T change found in the NSD1 gene.Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.096
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.75	P
Vest4		0.53
MutPred		0.13		Gain of phosphorylation at A24 (P = 0.0177);
MVP		0.76
MPC		0.34
ClinPred		0.68	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.22
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-176562174;