NM_016169.4:c.210T>C

Variant names:

• chr10-102509196-T-C
• rs35166585
• NM_016169.4:c.210T>C

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_016169.4(SUFU):​c.210T>C​(p.Tyr70Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,614,218 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: SUFU NM_016169.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.658
• Publications: 2 publications found

Genes affected

SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

SUFU Gene-Disease associations (from GenCC):

• medulloblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Illumina
• basal cell nevus syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• ocular motor apraxia, Cogan type

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• Joubert syndrome 32

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Joubert syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• apraxia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-102509196-T-C is Benign according to our data. Variant chr10-102509196-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.658 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0039 (594/152352) while in subpopulation AFR AF = 0.0136 (566/41578). AF 95% confidence interval is 0.0127. There are 6 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016169.4. 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
	SUFU	NM_016169.4	MANE Select	c.210T>C	p.Tyr70Tyr	synonymous	Exon 2 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.210T>C	p.Tyr70Tyr	synonymous	Exon 2 of 11	NP_001171604.1	Q9UMX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	ENST00000369902.8	TSL:1 MANE Select	c.210T>C	p.Tyr70Tyr	synonymous	Exon 2 of 12	ENSP00000358918.4	Q9UMX1-1
	SUFU	ENST00000423559.2	TSL:1	c.210T>C	p.Tyr70Tyr	synonymous	Exon 2 of 10	ENSP00000411597.2	Q9UMX1-3
	SUFU	ENST00000369899.6	TSL:1	c.210T>C	p.Tyr70Tyr	synonymous	Exon 2 of 11	ENSP00000358915.2	Q9UMX1-2

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152234 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00109 AC: 271 AN: 249054 AF XY: 0.000764

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.000366 AC XY: 266 AN XY: 727234

African (AFR) AF: 0.0136 AC: 456 AN: 33478

American (AMR) AF: 0.00114 AC: 51 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5750

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112010

Other (OTH) AF: 0.000878 AC: 53 AN: 60394

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152352 Hom.: 6 Cov.: 32 AF XY: 0.00342 AC XY: 255 AN XY: 74508

African (AFR) AF: 0.0136 AC: 566 AN: 41578

American (AMR) AF: 0.00105 AC: 16 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00281 Hom.: 3

Bravo AF: 0.00462

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Gorlin syndrome;C0025149:Medulloblastoma (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Medulloblastoma (1)
-	-	1	Medulloblastoma;C3551915:Familial meningioma;C4540342:Joubert syndrome 32;C5830451:Basal cell nevus syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.3
DANN	Benign	0.43
PhyloP100		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs35166585; hg19: chr10-104268953;