17-30196364-ATTTT-ATTT

Variant names:

• chr17-30196364-AT-A
• rs748194758
• NM_001045.6:c.*2091delA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001045.6(SLC6A4):​c.*2091delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 145,752 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (7 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: SLC6A4 NM_001045.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.516
• Publications: 0 publications found

Genes affected

SLC6A4 (HGNC:11050): (solute carrier family 6 member 4) This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]

SLC6A4 Gene-Disease associations (from GenCC):

• obsessive-compulsive disorder

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAd4 at 1098 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001045.6. 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
	SLC6A4	NM_001045.6	MANE Select	c.*2091delA		3_prime_UTR	Exon 15 of 15	NP_001036.1	P31645-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	ENST00000650711.1	MANE Select	c.*2091delA		3_prime_UTR	Exon 15 of 15	ENSP00000498537.1	P31645-1
	SLC6A4	ENST00000261707.7	TSL:1	c.*2091delA		3_prime_UTR	Exon 15 of 15	ENSP00000261707.3	P31645-1
	SLC6A4	ENST00000855098.1		c.*2091delA		splice_region	Exon 13 of 13	ENSP00000525157.1

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1095 AN: 145614 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00507

Gnomad ASJ AF: 0.0214

Gnomad EAS AF: 0.000595

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0100

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.00752

GnomAD4 exome AF: 0.100 AC: 9 AN: 90 Hom.: 0 Cov.: 0 AF XY: 0.0600 AC XY: 3 AN XY: 50

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.100 AC: 9 AN: 90

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00754 AC: 1098 AN: 145662 Hom.: 7 Cov.: 32 AF XY: 0.00802 AC XY: 567 AN XY: 70708

African (AFR) AF: 0.00835 AC: 335 AN: 40096

American (AMR) AF: 0.00507 AC: 74 AN: 14606

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 72 AN: 3366

East Asian (EAS) AF: 0.000596 AC: 3 AN: 5030

South Asian (SAS) AF: 0.00217 AC: 10 AN: 4614

European-Finnish (FIN) AF: 0.0248 AC: 222 AN: 8946

Middle Eastern (MID) AF: 0.0144 AC: 4 AN: 278

European-Non Finnish (NFE) AF: 0.00552 AC: 363 AN: 65816

Other (OTH) AF: 0.00746 AC: 15 AN: 2012

Alfa AF: 0.00149 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52
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: rs748194758; hg19: chr17-28523382; COSMIC: COSV55564890; COSMIC: COSV55564890;