14-73276596-C-T

Variant names:

• chr14-73276596-C-T
• rs117957039
• NM_001005743.2:c.1938G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001005743.2(NUMB):​c.1938G>A​(p.Thr646Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,612,212 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: NUMB NM_001005743.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.78
• Publications: 1 publications found

Genes affected

NUMB (HGNC:8060): (NUMB endocytic adaptor protein) The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 14-73276596-C-T is Benign according to our data. Variant chr14-73276596-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2644361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BS2: High AC in GnomAd4 at 236 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005743.2. 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
	NUMB	NM_001005743.2	MANE Select	c.1938G>A	p.Thr646Thr	synonymous	Exon 13 of 13	NP_001005743.1	P49757-1
	NUMB	NM_003744.6		c.1905G>A	p.Thr635Thr	synonymous	Exon 12 of 12	NP_003735.3
	NUMB	NM_001005744.2		c.1794G>A	p.Thr598Thr	synonymous	Exon 12 of 12	NP_001005744.1	P49757-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMB	ENST00000555238.6	TSL:1 MANE Select	c.1938G>A	p.Thr646Thr	synonymous	Exon 13 of 13	ENSP00000451300.1	P49757-1
	NUMB	ENST00000557597.5	TSL:1	c.1905G>A	p.Thr635Thr	synonymous	Exon 12 of 12	ENSP00000451117.1	P49757-3
	NUMB	ENST00000356296.8	TSL:1	c.1794G>A	p.Thr598Thr	synonymous	Exon 12 of 12	ENSP00000348644.4	P49757-2

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00167 AC: 418 AN: 250684 AF XY: 0.00171

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00851

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00204 AC: 2978 AN: 1459920 Hom.: 6 Cov.: 31 AF XY: 0.00207 AC XY: 1504 AN XY: 725964

African (AFR) AF: 0.000479 AC: 16 AN: 33418

American (AMR) AF: 0.000269 AC: 12 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00867 AC: 226 AN: 26066

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39636

South Asian (SAS) AF: 0.000801 AC: 69 AN: 86166

European-Finnish (FIN) AF: 0.000937 AC: 50 AN: 53372

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00226 AC: 2512 AN: 1110588

Other (OTH) AF: 0.00144 AC: 87 AN: 60306

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74474

African (AFR) AF: 0.000361 AC: 15 AN: 41564

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00145

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00178

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.11
DANN	Benign	0.79
PhyloP100		-2.8
Mutation Taster		=98/2	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: rs117957039; hg19: chr14-73743304; COSMIC: COSV53714668; COSMIC: COSV53714668;