rs199814669

Variant names:

• chr5-177211963-G-C
• rs199814669
• NM_022455.5:c.3564G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-177211963-G-C
• chr5-177211963-G-A

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.3564G>C​(p.Arg1188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,609,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. R1188K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.86
• Publications: 8 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=0.006217897).
• BP6: Variant 5-177211963-G-C is Benign according to our data. Variant chr5-177211963-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000401 (61/152108) while in subpopulation AMR AF = 0.00131 (20/15252). AF 95% confidence interval is 0.000868. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 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.3564G>C	p.Arg1188Ser	missense	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.3564G>C	p.Arg1188Ser	missense	Exon 5 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.3564G>C	p.Arg1188Ser	missense	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.3564G>C	p.Arg1188Ser	missense	Exon 5 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.2691G>C	p.Arg897Ser	missense	Exon 6 of 24	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.3564G>C	p.Arg1188Ser	missense	Exon 5 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000449 AC: 112 AN: 249698 AF XY: 0.000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.00495

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000364 AC: 531 AN: 1457764 Hom.: 0 Cov.: 37 AF XY: 0.000353 AC XY: 256 AN XY: 724718

African (AFR) AF: 0.0000301 AC: 1 AN: 33256

American (AMR) AF: 0.00102 AC: 45 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 141 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5730

European-Non Finnish (NFE) AF: 0.000265 AC: 294 AN: 1109420

Other (OTH) AF: 0.000814 AC: 49 AN: 60178

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152108 Hom.: 0 Cov.: 31 AF XY: 0.000390 AC XY: 29 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00131 AC: 20 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68028

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.000744 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.19		Loss of MoRF binding (P = 0.0315)
MVP		0.25
MPC		0.060
ClinPred		0.035	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.31
Mutation Taster		=91/9	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: rs199814669; hg19: chr5-176638964; COSMIC: COSV61774707;