5-177134112-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022455.5(NSD1):c.-18+160T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 148,406 control chromosomes in the GnomAD database, including 11,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (11506 hom., cov: 28)
  • Exomes 𝑓: 0.21 (1 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.158

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=-0.75).
• BP6: Variant 5-177134112-T-C is Benign according to our data. Variant chr5-177134112-T-C is described in ClinVar as [Benign]. Clinvar id is 1239366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.-18+160T>C		intron_variant		ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.-18+160T>C		intron_variant		1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 49435 AN: 148264 Hom.: 11486 Cov.: 28

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.0767

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.214 AC: 9 AN: 42 Hom.: 1 Cov.: 0 AF XY: 0.225 AC XY: 9 AN XY: 40

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.334 AC: 49498 AN: 148364 Hom.: 11506 Cov.: 28 AF XY: 0.335 AC XY: 24284 AN XY: 72436

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.307

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.290

Alfa AF: 0.276 Hom.: 988

Bravo AF: 0.352

Asia WGS AF: 0.397 AC: 1347 AN: 3408

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	14
Dann	Benign	0.14

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: rs3733873; hg19: chr5-176561113; COSMIC: COSV61780281; COSMIC: COSV61780281;