10-102599540-G-T

Variant names:

• chr10-102599540-G-T
• rs34135067
• NM_016169.4:c.1018G>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_016169.4(SUFU):​c.1018G>T​(p.Ala340Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,613,966 control chromosomes in the GnomAD database, including 57 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A340V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (54 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 2.71
• Publications: 22 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nevoid basal cell carcinoma syndrome

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

  Inheritance: AD Classification: STRONG Submitted by: G2P
• neurodevelopmental disorder

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

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

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

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007463455).
• BP6: Variant 10-102599540-G-T is Benign according to our data. Variant chr10-102599540-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00626 (953/152314) while in subpopulation NFE AF = 0.0101 (686/68028). AF 95% confidence interval is 0.00946. There are 3 homozygotes in GnomAd4. There are 464 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1018G>T	p.Ala340Ser	missense	Exon 8 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.1018G>T	p.Ala340Ser	missense	Exon 8 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.1018G>T	p.Ala340Ser	missense	Exon 8 of 12	ENSP00000358918.4	Q9UMX1-1
	SUFU	ENST00000423559.2	TSL:1	c.1018G>T	p.Ala340Ser	missense	Exon 8 of 10	ENSP00000411597.2	Q9UMX1-3
	SUFU	ENST00000369899.6	TSL:1	c.1018G>T	p.Ala340Ser	missense	Exon 8 of 11	ENSP00000358915.2	Q9UMX1-2

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 953 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00596 AC: 1496 AN: 251160 AF XY: 0.00580

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00782

Gnomad NFE exome AF: 0.00984

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00727 AC: 10630 AN: 1461652 Hom.: 54 Cov.: 31 AF XY: 0.00713 AC XY: 5185 AN XY: 727110

African (AFR) AF: 0.00128 AC: 43 AN: 33474

American (AMR) AF: 0.00382 AC: 171 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86256

European-Finnish (FIN) AF: 0.00856 AC: 457 AN: 53388

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00849 AC: 9441 AN: 1111844

Other (OTH) AF: 0.00719 AC: 434 AN: 60372

GnomAD4 genome AF: 0.00626 AC: 953 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74478

African (AFR) AF: 0.00144 AC: 60 AN: 41574

American (AMR) AF: 0.00666 AC: 102 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0101 AC: 686 AN: 68028

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00800 Hom.: 5

Bravo AF: 0.00560

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00605 AC: 734

EpiCase AF: 0.0118

EpiControl AF: 0.00818

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	3	not specified (4)
-	-	1	Familial meningioma (1)
-	-	1	Gorlin syndrome;C0025149:Medulloblastoma (1)
-	-	1	Gorlin syndrome;C0025149:Medulloblastoma;C3551915:Familial meningioma;C4540342:Joubert syndrome 32 (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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.044
Sift	Benign	0.98	T
Sift4G	Benign	0.84	T
Polyphen		0.15	B
Vest4		0.50
MVP		0.47
MPC		0.59
ClinPred		0.0074	T
GERP RS		3.3
Varity_R		0.023
gMVP		0.32
Mutation Taster		=95/5	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: rs34135067; hg19: chr10-104359297; COSMIC: COSV64014005;