rs77093936

Variant names:

• chr5-177135442-C-T
• rs77093936
• NM_022455.5:c.339C>T

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.339C>T​(p.Cys113Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,614,146 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (51 hom.)
• Consequence: NSD1 NM_022455.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.46
• Publications: 6 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: Orphanet, G2P, ClinGen
• 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=-0.61).
• BP6: Variant 5-177135442-C-T is Benign according to our data. Variant chr5-177135442-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00191 (291/152302) while in subpopulation EAS AF = 0.0268 (139/5194). AF 95% confidence interval is 0.0231. There are 4 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 291 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.339C>T	p.Cys113Cys	synonymous	Exon 2 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.339C>T	p.Cys113Cys	synonymous	Exon 2 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.339C>T	p.Cys113Cys	synonymous	Exon 2 of 23	NP_001396231.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.339C>T	p.Cys113Cys	synonymous	Exon 2 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.-37+242C>T		intron	N/A	ENSP00000343209.5
	NSD1	ENST00000602285.1	TSL:1	n.511C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152184 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00472 AC: 1186 AN: 251422 AF XY: 0.00510

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0242

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00178 AC: 2595 AN: 1461844 Hom.: 51 Cov.: 32 AF XY: 0.00209 AC XY: 1522 AN XY: 727224

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0180 AC: 714 AN: 39700

South Asian (SAS) AF: 0.0148 AC: 1276 AN: 86252

European-Finnish (FIN) AF: 0.00453 AC: 242 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111996

Other (OTH) AF: 0.00339 AC: 205 AN: 60396

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152302 Hom.: 4 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74484

African (AFR) AF: 0.000144 AC: 6 AN: 41552

American (AMR) AF: 0.000719 AC: 11 AN: 15298

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

East Asian (EAS) AF: 0.0268 AC: 139 AN: 5194

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4826

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000924 Hom.: 0

Bravo AF: 0.00128

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Sotos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		2.5
PromoterAI		0.00060	Neutral
Mutation Taster		=96/4	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: rs77093936; hg19: chr5-176562443; COSMIC: COSV61771464; COSMIC: COSV61771464;