rs79098301

chr5-177280543-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022455.5(NSD1):c.5623-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,613,924 control chromosomes in the GnomAD database, including 2,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (200 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2309 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.49

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-177280543-G-A is Benign according to our data. Variant chr5-177280543-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177280543-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.5623-22G>A		intron_variant		ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.5623-22G>A		intron_variant		1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7408 AN: 152196 Hom.: 199 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0467 AC: 11660 AN: 249900 Hom.: 350 AF XY: 0.0485 AC XY: 6564 AN XY: 135240

Gnomad AFR exome AF: 0.0593

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.0190

Gnomad SAS exome AF: 0.0859

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0500

Gnomad OTH exome AF: 0.0469

GnomAD4 exome AF: 0.0518 AC: 75708 AN: 1461610 Hom.: 2309 Cov.: 32 AF XY: 0.0528 AC XY: 38364 AN XY: 727132

Gnomad4 AFR exome AF: 0.0569

Gnomad4 AMR exome AF: 0.0218

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.0173

Gnomad4 SAS exome AF: 0.0836

Gnomad4 FIN exome AF: 0.0446

Gnomad4 NFE exome AF: 0.0527

Gnomad4 OTH exome AF: 0.0515

GnomAD4 genome AF: 0.0487 AC: 7417 AN: 152314 Hom.: 200 Cov.: 32 AF XY: 0.0478 AC XY: 3560 AN XY: 74468

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0177

Gnomad4 SAS AF: 0.0814

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.0515

Gnomad4 OTH AF: 0.0458

Alfa AF: 0.0498 Hom.: 42

Bravo AF: 0.0469

Asia WGS AF: 0.0930 AC: 324 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Sotos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.0020
Dann	Benign	0.62

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: rs79098301; hg19: chr5-176707544;