5-177294118-G-A

Variant names:

• chr5-177294118-G-A
• rs35848863
• NM_022455.5:c.6750G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022455.5(NSD1):​c.6750G>A​(p.Met2250Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0516 in 1,614,000 control chromosomes in the GnomAD database, including 2,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.049 (199 hom., cov: 30)
  • Exomes 𝑓: 0.052 (2308 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0770
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012430251).
• BP6: Variant 5-177294118-G-A is Benign according to our data. Variant chr5-177294118-G-A is described in ClinVar as Benign. ClinVar VariationId is 96070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	NM_022455.5	MANE Select	c.6750G>A	p.Met2250Ile	missense	Exon 23 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.6750G>A	p.Met2250Ile	missense	Exon 23 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.6750G>A	p.Met2250Ile	missense	Exon 23 of 23	NP_001396231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.6750G>A	p.Met2250Ile	missense	Exon 23 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.5877G>A	p.Met1959Ile	missense	Exon 24 of 24	ENSP00000343209.5
	NSD1	ENST00000687453.1		c.6441G>A	p.Met2147Ile	missense	Exon 20 of 20	ENSP00000508426.1

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7401 AN: 152058 Hom.: 198 Cov.: 30

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0818

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0515

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0467 AC: 11724 AN: 251202 AF XY: 0.0485

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0191

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.0501

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0519 AC: 75817 AN: 1461824 Hom.: 2308 Cov.: 34 AF XY: 0.0528 AC XY: 38398 AN XY: 727208

African (AFR) AF: 0.0570 AC: 1910 AN: 33480

American (AMR) AF: 0.0218 AC: 974 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 507 AN: 26136

East Asian (EAS) AF: 0.0173 AC: 688 AN: 39700

South Asian (SAS) AF: 0.0837 AC: 7217 AN: 86258

European-Finnish (FIN) AF: 0.0446 AC: 2378 AN: 53378

Middle Eastern (MID) AF: 0.0671 AC: 387 AN: 5768

European-Non Finnish (NFE) AF: 0.0527 AC: 58639 AN: 1111986

Other (OTH) AF: 0.0516 AC: 3117 AN: 60394

GnomAD4 genome AF: 0.0487 AC: 7410 AN: 152176 Hom.: 199 Cov.: 30 AF XY: 0.0478 AC XY: 3556 AN XY: 74392

African (AFR) AF: 0.0549 AC: 2278 AN: 41500

American (AMR) AF: 0.0326 AC: 498 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5176

South Asian (SAS) AF: 0.0816 AC: 393 AN: 4814

European-Finnish (FIN) AF: 0.0418 AC: 443 AN: 10598

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0515 AC: 3503 AN: 68004

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0495 Hom.: 746

Bravo AF: 0.0469

TwinsUK AF: 0.0580 AC: 215

ALSPAC AF: 0.0498 AC: 192

ESP6500AA AF: 0.0590 AC: 260

ESP6500EA AF: 0.0488 AC: 420

ExAC AF: 0.0492 AC: 5970

Asia WGS AF: 0.0930 AC: 324 AN: 3478

EpiCase AF: 0.0491

EpiControl AF: 0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jun 13, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Sotos syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.077
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.066
Sift	Benign	0.043	D
Sift4G	Benign	0.17	T
Polyphen		0.095	B
Vest4		0.11
MutPred		0.057		Loss of catalytic residue at M2250 (P = 0.0214)
MPC		0.16
ClinPred		0.0019	T
GERP RS		1.5
Varity_R		0.070
gMVP		0.12
Mutation Taster		=97/3	polymorphism (auto)

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: rs35848863; hg19: chr5-176721119; COSMIC: COSV61770840; COSMIC: COSV61770840;