5-177288805-G-T

Variant names:

• chr5-177288805-G-T
• rs587784182
• NM_022455.5:c.6152-14G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022455.5(NSD1):​c.6152-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,401,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• Publications: 0 publications found

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]

NSD1 Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome due to NSD1 mutation

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Sotos syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• Sotos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	NM_022455.5	MANE Select	c.6152-14G>T		intron	N/A	NP_071900.2
	NSD1	NM_001409301.1		c.6152-14G>T		intron	N/A	NP_001396230.1
	NSD1	NM_001409302.1		c.6152-14G>T		intron	N/A	NP_001396231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.6152-14G>T		intron	N/A	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.5279-14G>T		intron	N/A	ENSP00000343209.5
	NSD1	ENST00000513736.1	TSL:5	n.280G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1401400 Hom.: 0 Cov.: 24 AF XY: 0.00000285 AC XY: 2 AN XY: 700904

African (AFR) AF: 0.00 AC: 0 AN: 32234

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1056980

Other (OTH) AF: 0.00 AC: 0 AN: 58366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		-0.29

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

Other links and lift over

dbSNP: rs587784182; hg19: chr5-176715806;