5-177248165-ATT-AT

Position:

• chr5-177248165-ATT-AT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022455.5(NSD1):​c.4498-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,718 control chromosomes in the GnomAD database, including 534 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Exomes 𝑓: 0.023 (503 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.52

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 -16 ACMG points.

• BP6: Variant 5-177248165-AT-A is Benign according to our data. Variant chr5-177248165-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 96059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177248165-AT-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0168 (2550/152224) while in subpopulation NFE AF= 0.0273 (1855/68020). AF 95% confidence interval is 0.0262. There are 31 homozygotes in gnomad4. There are 1212 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5	c.4498-10delT		intron_variant		ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.4498-15delT		intron_variant		1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2553 AN: 152106 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.00961

GnomAD3 exomes AF: 0.0169 AC: 4237 AN: 250542 Hom.: 55 AF XY: 0.0170 AC XY: 2300 AN XY: 135406

Gnomad AFR exome AF: 0.00463

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0233 AC: 34034 AN: 1461494 Hom.: 503 Cov.: 32 AF XY: 0.0230 AC XY: 16696 AN XY: 727004

Gnomad4 AFR exome AF: 0.00329

Gnomad4 AMR exome AF: 0.00677

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0168 AC: 2550 AN: 152224 Hom.: 31 Cov.: 32 AF XY: 0.0163 AC XY: 1212 AN XY: 74422

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0300

Gnomad4 NFE AF: 0.0273

Gnomad4 OTH AF: 0.00951

Alfa AF: 0.0138 Hom.: 7

Bravo AF: 0.0140

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Sotos syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200890017; hg19: chr5-176675166;