rs78247455

Variant names:

• chr5-177295004-G-A
• rs78247455
• NM_022455.5:c.7636G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022455.5(NSD1):​c.7636G>A​(p.Ala2546Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,614,198 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.026 (620 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.41
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016538799).
• BP6: Variant 5-177295004-G-A is Benign according to our data. Variant chr5-177295004-G-A is described in ClinVar as Benign. ClinVar VariationId is 96079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

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.7636G>A	p.Ala2546Thr	missense	Exon 23 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.7636G>A	p.Ala2546Thr	missense	Exon 23 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.7636G>A	p.Ala2546Thr	missense	Exon 23 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.7636G>A	p.Ala2546Thr	missense	Exon 23 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.6763G>A	p.Ala2255Thr	missense	Exon 24 of 24	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.7636G>A	p.Ala2546Thr	missense	Exon 23 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3484 AN: 152194 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0238 AC: 5980 AN: 250880 AF XY: 0.0254

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0189

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0256 AC: 37399 AN: 1461886 Hom.: 620 Cov.: 34 AF XY: 0.0264 AC XY: 19218 AN XY: 727244

African (AFR) AF: 0.0254 AC: 850 AN: 33480

American (AMR) AF: 0.0116 AC: 520 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26136

East Asian (EAS) AF: 0.0170 AC: 674 AN: 39700

South Asian (SAS) AF: 0.0537 AC: 4629 AN: 86258

European-Finnish (FIN) AF: 0.0136 AC: 726 AN: 53418

Middle Eastern (MID) AF: 0.0304 AC: 175 AN: 5766

European-Non Finnish (NFE) AF: 0.0252 AC: 28073 AN: 1112008

Other (OTH) AF: 0.0273 AC: 1647 AN: 60396

GnomAD4 genome AF: 0.0229 AC: 3494 AN: 152312 Hom.: 54 Cov.: 32 AF XY: 0.0227 AC XY: 1694 AN XY: 74492

African (AFR) AF: 0.0248 AC: 1030 AN: 41562

American (AMR) AF: 0.0213 AC: 326 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.0171 AC: 89 AN: 5194

South Asian (SAS) AF: 0.0543 AC: 262 AN: 4828

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1573 AN: 68018

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0240 Hom.: 136

Bravo AF: 0.0230

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.0237 AC: 204

ExAC AF: 0.0255 AC: 3095

Asia WGS AF: 0.0700 AC: 244 AN: 3478

EpiCase AF: 0.0212

EpiControl AF: 0.0226

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Sotos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.023
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0017	T
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.079	T
Polyphen		0.62	P
Vest4		0.092
MPC		0.14
ClinPred		0.0097	T
GERP RS		3.8
Varity_R		0.074
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs78247455; hg19: chr5-176722005; COSMIC: COSV107427776; COSMIC: COSV107427776;