NM_138927.4:c.78-9C>T

Variant names:

• chr21-33546204-C-T
• rs201007642
• NM_138927.4:c.78-9C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_138927.4(SON):​c.78-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,583,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SON NM_138927.4 intron
• Scores: Splicing: ADA: 0.9861
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.658
• Publications: 0 publications found

Genes affected

SON (HGNC:11183): (SON DNA and RNA binding protein) This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

SON Gene-Disease associations (from GenCC):

• ZTTK syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Illumina, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 21-33546204-C-T is Benign according to our data. Variant chr21-33546204-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1722479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138927.4. 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
	SON	NM_138927.4	MANE Select	c.78-9C>T		intron	N/A	NP_620305.3	P18583-1
	SON	NM_032195.3		c.78-9C>T		intron	N/A	NP_115571.3	P18583-3
	SON	NM_001291411.2		c.78-9C>T		intron	N/A	NP_001278340.2	P18583-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SON	ENST00000356577.10	TSL:1 MANE Select	c.78-9C>T		intron	N/A	ENSP00000348984.4	P18583-1
	SON	ENST00000300278.8	TSL:1	c.78-9C>T		intron	N/A	ENSP00000300278.2	P18583-3
	SON	ENST00000381692.6	TSL:1	c.78-9C>T		intron	N/A	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1431496 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 10 AN XY: 711524

African (AFR) AF: 0.00 AC: 0 AN: 31494

American (AMR) AF: 0.00 AC: 0 AN: 35442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 80528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1102010

Other (OTH) AF: 0.00 AC: 0 AN: 59154

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74274

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.80
PhyloP100		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.70

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201007642; hg19: chr21-34918510;