rs148719957

Variant names:

• chr21-37188565-C-G
• rs148719957
• NM_001330683.2:c.4994C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-37188565-C-G
• chr21-37188565-C-A
• chr21-37188565-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001330683.2(TTC3):​c.4994C>G​(p.Ala1665Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,613,918 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: TTC3 NM_001330683.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0950
• Publications: 6 publications found

Genes affected

TTC3 (HGNC:12393): (tetratricopeptide repeat domain 3) Enables ubiquitin-protein transferase activity. Involved in protein K48-linked ubiquitination and ubiquitin-dependent protein catabolic process. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TTC3-AS1 (HGNC:40595): (TTC3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003087908).
• BP6: Variant 21-37188565-C-G is Benign according to our data. Variant chr21-37188565-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 773091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330683.2. 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
	TTC3	NM_001330683.2	MANE Select	c.4994C>G	p.Ala1665Gly	missense	Exon 39 of 46	NP_001317612.1	P53804-1
	TTC3	NM_001320703.2		c.5114C>G	p.Ala1705Gly	missense	Exon 40 of 47	NP_001307632.1
	TTC3	NM_001320704.2		c.5048C>G	p.Ala1683Gly	missense	Exon 40 of 47	NP_001307633.1	H7BZ57

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC3	ENST00000418766.6	TSL:5 MANE Select	c.4994C>G	p.Ala1665Gly	missense	Exon 39 of 46	ENSP00000403943.2	P53804-1
	TTC3	ENST00000354749.6	TSL:1	c.4994C>G	p.Ala1665Gly	missense	Exon 38 of 45	ENSP00000346791.2	P53804-1
	TTC3	ENST00000399017.6	TSL:1	c.4994C>G	p.Ala1665Gly	missense	Exon 39 of 46	ENSP00000381981.2	P53804-1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000617 AC: 155 AN: 251394 AF XY: 0.000640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000285 AC: 417 AN: 1461774 Hom.: 3 Cov.: 30 AF XY: 0.000308 AC XY: 224 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39682

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000188 AC: 209 AN: 1111930

Other (OTH) AF: 0.000480 AC: 29 AN: 60388

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74366

African (AFR) AF: 0.0000482 AC: 2 AN: 41502

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5158

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000327

EpiControl AF: 0.000533

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
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.095
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.27	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.071
MVP		0.20
MPC		0.089
ClinPred		0.0071	T
GERP RS		-0.33
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.043
gMVP		0.058
Mutation Taster		=98/2	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: rs148719957; hg19: chr21-38560866;