chr5-177135863-C-T

Variant names:

• chr5-177135863-C-T
• rs149334244
• NM_022455.5:c.760C>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.760C>T​(p.Leu254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,606,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.12
• Publications: 4 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=0.008291572).
• BP6: Variant 5-177135863-C-T is Benign according to our data. Variant chr5-177135863-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00141 (214/152302) while in subpopulation AFR AF = 0.00493 (205/41558). AF 95% confidence interval is 0.00438. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 214 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.760C>T	p.Leu254Phe	missense	Exon 2 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.760C>T	p.Leu254Phe	missense	Exon 2 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.760C>T	p.Leu254Phe	missense	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.760C>T	p.Leu254Phe	missense	Exon 2 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.-36-78C>T		intron	N/A	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000602285.1	TSL:1	n.932C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000478

GnomAD2 exomes AF: 0.000352 AC: 88 AN: 249800 AF XY: 0.000222

Gnomad AFR exome AF: 0.00488

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1453920 Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 77 AN XY: 721606

African (AFR) AF: 0.00422 AC: 140 AN: 33180

American (AMR) AF: 0.000339 AC: 15 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 85708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.00000633 AC: 7 AN: 1106162

Other (OTH) AF: 0.000250 AC: 15 AN: 60014

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74470

African (AFR) AF: 0.00493 AC: 205 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15298

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.00148

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000453 AC: 55

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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)
-	-	1	Inborn genetic diseases (1)
-	-	1	NSD1-related disorder (1)
-	-	1	Sotos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	0.55	N
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	D
Sift4G	Benign	0.73	T
Polyphen		0.44	B
Vest4		0.34
MVP		0.41
MPC		0.25
ClinPred		0.0089	T
GERP RS		4.9
Varity_R		0.093
gMVP		0.29
Mutation Taster		=77/23	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: rs149334244; hg19: chr5-176562864;