rs145987330

Variant names:

• chr5-177211234-T-C
• rs145987330
• NM_022455.5:c.2835T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022455.5(NSD1):​c.2835T>C​(p.Ser945Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,018 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: NSD1 NM_022455.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.00200
• Publications: 2 publications found

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]

NSD1 Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome due to NSD1 mutation

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Sotos syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
• Sotos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-177211234-T-C is Benign according to our data. Variant chr5-177211234-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.002 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00134 (204/152312) while in subpopulation NFE AF = 0.000706 (48/68026). AF 95% confidence interval is 0.000547. There are 2 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 204 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	NM_022455.5	MANE Select	c.2835T>C	p.Ser945Ser	synonymous	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.2835T>C	p.Ser945Ser	synonymous	Exon 5 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.2835T>C	p.Ser945Ser	synonymous	Exon 5 of 23	NP_001396231.1	Q96L73-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.2835T>C	p.Ser945Ser	synonymous	Exon 5 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.1962T>C	p.Ser654Ser	synonymous	Exon 6 of 24	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.2835T>C	p.Ser945Ser	synonymous	Exon 5 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00212 AC: 532 AN: 250384 AF XY: 0.00230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000990

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00119 AC: 1733 AN: 1461706 Hom.: 18 Cov.: 37 AF XY: 0.00126 AC XY: 918 AN XY: 727146

African (AFR) AF: 0.000209 AC: 7 AN: 33474

American (AMR) AF: 0.000336 AC: 15 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 985 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000416 AC: 462 AN: 1111908

Other (OTH) AF: 0.00361 AC: 218 AN: 60386

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74476

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00283 Hom.: 4

Bravo AF: 0.00131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Sotos syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	NSD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.41
PhyloP100		0.0020
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs145987330; hg19: chr5-176638235; COSMIC: COSV61778976; COSMIC: COSV61778976;