chr5-177135583-C-T

Variant names:

• chr5-177135583-C-T
• rs79427433
• NM_022455.5:c.480C>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.480C>T​(p.Asp160Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,614,056 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (8 hom.)
• Consequence: NSD1 NM_022455.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.59
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 5-177135583-C-T is Benign according to our data. Variant chr5-177135583-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000802 (122/152182) while in subpopulation EAS AF = 0.0214 (111/5184). AF 95% confidence interval is 0.0182. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 122 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.480C>T	p.Asp160Asp	synonymous	Exon 2 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.480C>T	p.Asp160Asp	synonymous	Exon 2 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.480C>T	p.Asp160Asp	synonymous	Exon 2 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.480C>T	p.Asp160Asp	synonymous	Exon 2 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.-36-358C>T		intron	N/A	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000602285.1	TSL:1	n.652C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00203 AC: 510 AN: 251356 AF XY: 0.00191

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0268

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000580 AC: 848 AN: 1461874 Hom.: 8 Cov.: 32 AF XY: 0.000576 AC XY: 419 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0182 AC: 721 AN: 39698

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112006

Other (OTH) AF: 0.00136 AC: 82 AN: 60396

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74404

African (AFR) AF: 0.0000241 AC: 1 AN: 41510

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

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

East Asian (EAS) AF: 0.0214 AC: 111 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000382 Hom.: 0

Bravo AF: 0.00113

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Sotos syndrome (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	NSD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		1.6
PromoterAI		0.0062	Neutral
Mutation Taster		=100/0	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: rs79427433; hg19: chr5-176562584; COSMIC: COSV61787531; COSMIC: COSV61787531;