rs121908068

Variant names:

• chr5-177292124-C-G
• rs121908068
• NM_022455.5:c.6429C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-177292124-C-G
• chr5-177292124-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_022455.5(NSD1):​c.6429C>G​(p.His2143Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -1.39

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a zinc_finger_region PHD-type 4; atypical (size 47) in uniprot entity NSD1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_022455.5
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 5-177292124-C-G is Pathogenic according to our data. Variant chr5-177292124-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4139.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-177292124-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.6429C>G	p.His2143Gln	missense_variant	Exon 22 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.6429C>G	p.His2143Gln	missense_variant	Exon 22 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sotos syndrome Pathogenic:1

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;D;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.28	N
LIST_S2	Pathogenic	1.0	D;D;.
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.98		.;Gain of ubiquitination at K2140 (P = 0.0688);.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		-5.1
Varity_R		0.74
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908068; hg19: chr5-176719125;