rs201483724

Variant names:

• chr5-177248247-G-A
• rs201483724
• NM_022455.5:c.4564G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-177248247-G-A
• chr5-177248247-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022455.5(NSD1):​c.4564G>A​(p.Asp1522Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000372 in 1,614,128 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1522Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (10 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.72
• Publications: 7 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=0.0038702786).
• BP6: Variant 5-177248247-G-A is Benign according to our data. Variant chr5-177248247-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000249 (38/152310) while in subpopulation SAS AF = 0.00621 (30/4828). AF 95% confidence interval is 0.00447. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 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.4564G>A	p.Asp1522Asn	missense	Exon 11 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.4564G>A	p.Asp1522Asn	missense	Exon 11 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.4564G>A	p.Asp1522Asn	missense	Exon 11 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.4564G>A	p.Asp1522Asn	missense	Exon 11 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.3691G>A	p.Asp1231Asn	missense	Exon 12 of 24	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.4564G>A	p.Asp1522Asn	missense	Exon 11 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000629 AC: 158 AN: 251192 AF XY: 0.000854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000384 AC: 562 AN: 1461818 Hom.: 10 Cov.: 32 AF XY: 0.000558 AC XY: 406 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00516 AC: 445 AN: 86240

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111984

Other (OTH) AF: 0.000480 AC: 29 AN: 60394

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0039	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.97	L
PhyloP100		5.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.16	T
Polyphen		0.73	P
Vest4		0.22
MVP		0.83
MPC		0.85
ClinPred		0.061	T
GERP RS		5.2
Varity_R		0.074
gMVP		0.54
Mutation Taster		=97/3	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: rs201483724; hg19: chr5-176675248;