NM_138927.4:c.111A>G

Variant names:

• chr21-33546246-A-G
• rs76600419
• NM_138927.4:c.111A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_138927.4(SON):​c.111A>G​(p.Thr37Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,613,448 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: SON NM_138927.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36
• 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: G2P, Orphanet, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 21-33546246-A-G is Benign according to our data. Variant chr21-33546246-A-G is described in ClinVar as Benign. ClinVar VariationId is 720940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00178 (271/152312) while in subpopulation AFR AF = 0.00628 (261/41552). AF 95% confidence interval is 0.00566. There are 2 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 271 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.111A>G	p.Thr37Thr	synonymous	Exon 2 of 12	NP_620305.3	P18583-1
	SON	NM_032195.3		c.111A>G	p.Thr37Thr	synonymous	Exon 2 of 7	NP_115571.3	P18583-3
	SON	NM_001291411.2		c.111A>G	p.Thr37Thr	synonymous	Exon 2 of 5	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.111A>G	p.Thr37Thr	synonymous	Exon 2 of 12	ENSP00000348984.4	P18583-1
	SON	ENST00000300278.8	TSL:1	c.111A>G	p.Thr37Thr	synonymous	Exon 2 of 7	ENSP00000300278.2	P18583-3
	SON	ENST00000381692.6	TSL:1	c.111A>G	p.Thr37Thr	synonymous	Exon 2 of 11	ENSP00000371111.2	J3QSZ5

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152194 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000375 AC: 94 AN: 250732 AF XY: 0.000273

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461136 Hom.: 1 Cov.: 30 AF XY: 0.000133 AC XY: 97 AN XY: 726894

African (AFR) AF: 0.00616 AC: 206 AN: 33440

American (AMR) AF: 0.000202 AC: 9 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111770

Other (OTH) AF: 0.000315 AC: 19 AN: 60378

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152312 Hom.: 2 Cov.: 33 AF XY: 0.00160 AC XY: 119 AN XY: 74478

African (AFR) AF: 0.00628 AC: 261 AN: 41552

American (AMR) AF: 0.000392 AC: 6 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000850 Hom.: 0

Bravo AF: 0.00196

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.57
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs76600419; hg19: chr21-34918552;