rs28932176

chr5-177210191-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022455.5(NSD1):c.1792T>C(p.Leu598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,600,966 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (234 hom.)
• Consequence: NSD1 NM_022455.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.33

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 5-177210191-T-C is Benign according to our data. Variant chr5-177210191-T-C is described in ClinVar as [Benign]. Clinvar id is 96040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210191-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.33 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.1792T>C	p.Leu598=	synonymous_variant	5/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.1792T>C	p.Leu598=	synonymous_variant	5/23	1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 976 AN: 152160 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0121 AC: 2877 AN: 238398 Hom.: 59 AF XY: 0.0144 AC XY: 1859 AN XY: 129328

Gnomad AFR exome AF: 0.000780

Gnomad AMR exome AF: 0.00378

Gnomad ASJ exome AF: 0.0444

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.0542

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00849 AC: 12297 AN: 1448688 Hom.: 234 Cov.: 38 AF XY: 0.00983 AC XY: 7076 AN XY: 719718

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00379

Gnomad4 ASJ exome AF: 0.0426

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00522

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152278 Hom.: 11 Cov.: 32 AF XY: 0.00628 AC XY: 468 AN XY: 74470

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0510

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00638

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00818 Hom.: 11

Bravo AF: 0.00509

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Sotos syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	9.2
Dann	Benign	0.66

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: rs28932176; hg19: chr5-176637192; COSMIC: COSV61775386; COSMIC: COSV61775386;