rs139601377

Positions:

• chr5-177244296-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022455.5(NSD1):​c.4378+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,502,434 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.304

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=-0.9).
• BP6: Variant 5-177244296-C-T is Benign according to our data. Variant chr5-177244296-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00184 (280/152214) while in subpopulation NFE AF= 0.00309 (210/68010). AF 95% confidence interval is 0.00275. There are 1 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 280 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.4378+26C>T		intron_variant		ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.4378+26C>T		intron_variant		1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00198 AC: 485 AN: 245318 Hom.: 0 AF XY: 0.00196 AC XY: 259 AN XY: 132416

Gnomad AFR exome AF: 0.000563

Gnomad AMR exome AF: 0.000880

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00296 AC: 4000 AN: 1350220 Hom.: 8 Cov.: 21 AF XY: 0.00291 AC XY: 1972 AN XY: 677182

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000880

Gnomad4 ASJ exome AF: 0.00248

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.000640

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74418

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.000289 AC: 1 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

Sep 08, 2020

- -

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	-0.90
CADD	Benign	0.72
DANN	Benign	0.82

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: rs139601377; hg19: chr5-176671297;