NM_022455.5:c.6887T>C

Variant names:

• chr5-177294255-T-C
• rs754309202
• NM_022455.5:c.6887T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_022455.5(NSD1):​c.6887T>C​(p.Val2296Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.144
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08494654).
• BP6: Variant 5-177294255-T-C is Benign according to our data. Variant chr5-177294255-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195775.
• BS2: High AC in GnomAdExome4 at 20 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.6887T>C	p.Val2296Ala	missense	Exon 23 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.6887T>C	p.Val2296Ala	missense	Exon 23 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.6887T>C	p.Val2296Ala	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.6887T>C	p.Val2296Ala	missense	Exon 23 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.6014T>C	p.Val2005Ala	missense	Exon 24 of 24	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.6887T>C	p.Val2296Ala	missense	Exon 23 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250632 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461216 Hom.: 0 Cov.: 39 AF XY: 0.0000206 AC XY: 15 AN XY: 726894

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111498

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000331 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.14
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.20
Sift	Benign	0.19	T
Sift4G	Benign	0.34	T
Polyphen		0.038	B
Vest4		0.12
MutPred		0.21		Loss of stability (P = 0.0038)
MVP		0.50
MPC		0.20
ClinPred		0.021	T
GERP RS		2.7
Varity_R		0.022
gMVP		0.16
Mutation Taster		=73/27	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: rs754309202; hg19: chr5-176721256;