rs111663030

chr5-177212217-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022455.5(NSD1):c.3796+22A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 857,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.167

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-177212217-A-T is Benign according to our data. Variant chr5-177212217-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 261585.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177212217-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00147 (1122/761754) while in subpopulation NFE AF= 0.00187 (1031/551856). AF 95% confidence interval is 0.00177. There are 1 homozygotes in gnomad4_exome. There are 537 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.3796+22A>T		intron_variant		ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.3796+22A>T		intron_variant		1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.000745 AC: 71 AN: 95330 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000948

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00256 AC: 161 AN: 62938 Hom.: 6 AF XY: 0.00230 AC XY: 79 AN XY: 34332

Gnomad AFR exome AF: 0.000845

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.000899

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00147 AC: 1122 AN: 761754 Hom.: 1 Cov.: 30 AF XY: 0.00140 AC XY: 537 AN XY: 383948

Gnomad4 AFR exome AF: 0.000214

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.000215

Gnomad4 EAS exome AF: 0.0000330

Gnomad4 SAS exome AF: 0.000206

Gnomad4 FIN exome AF: 0.000295

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000745 AC: 71 AN: 95354 Hom.: 0 Cov.: 26 AF XY: 0.000812 AC XY: 37 AN XY: 45554

Gnomad4 AFR AF: 0.000499

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000948

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.0
Dann	Benign	0.45

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: rs111663030; hg19: chr5-176639218;