rs12944821

Variant names:

• chr17-37596344-G-C
• rs12944821
• NM_007247.6:c.119C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007247.6(SYNRG):​c.119C>G​(p.Ala40Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,542 control chromosomes in the GnomAD database, including 29,075 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2686 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26389 hom.)
• Consequence: SYNRG NM_007247.6 missense, splice_region
• Scores: Splicing: ADA: 0.003344
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 21 publications found

Genes affected

SYNRG (HGNC:557): (synergin gamma) This gene encodes a protein that interacts with the gamma subunit of AP1 clathrin-adaptor complex. The AP1 complex is located at the trans-Golgi network and associates specific proteins with clathrin-coated vesicles. This encoded protein may act to connect the AP1 complex to other proteins. Alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013802052).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007247.6. 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
	SYNRG	NM_007247.6	MANE Select	c.119C>G	p.Ala40Gly	missense splice_region	Exon 3 of 22	NP_009178.3
	SYNRG	NM_001405103.1		c.119C>G	p.Ala40Gly	missense splice_region	Exon 3 of 24	NP_001392032.1
	SYNRG	NM_198882.3		c.119C>G	p.Ala40Gly	missense splice_region	Exon 3 of 22	NP_942583.1	Q9UMZ2-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNRG	ENST00000612223.5	TSL:1 MANE Select	c.119C>G	p.Ala40Gly	missense splice_region	Exon 3 of 22	ENSP00000483453.1	Q9UMZ2-1
	SYNRG	ENST00000622045.4	TSL:1	c.119C>G	p.Ala40Gly	missense splice_region	Exon 3 of 22	ENSP00000483063.1	Q9UMZ2-7
	SYNRG	ENST00000621136.4	TSL:1	c.119C>G	p.Ala40Gly	missense splice_region	Exon 3 of 20	ENSP00000484529.1	Q9UMZ2-4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27643 AN: 152064 Hom.: 2675 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.201 AC: 50485 AN: 250704 AF XY: 0.197

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.185 AC: 270299 AN: 1460360 Hom.: 26389 Cov.: 32 AF XY: 0.184 AC XY: 133838 AN XY: 726548

African (AFR) AF: 0.131 AC: 4364 AN: 33426

American (AMR) AF: 0.344 AC: 15345 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4429 AN: 26094

East Asian (EAS) AF: 0.214 AC: 8486 AN: 39674

South Asian (SAS) AF: 0.183 AC: 15788 AN: 86178

European-Finnish (FIN) AF: 0.152 AC: 8101 AN: 53288

Middle Eastern (MID) AF: 0.207 AC: 1195 AN: 5766

European-Non Finnish (NFE) AF: 0.181 AC: 201221 AN: 1111042

Other (OTH) AF: 0.188 AC: 11370 AN: 60348

GnomAD4 genome AF: 0.182 AC: 27661 AN: 152182 Hom.: 2686 Cov.: 33 AF XY: 0.182 AC XY: 13566 AN XY: 74412

African (AFR) AF: 0.137 AC: 5705 AN: 41532

American (AMR) AF: 0.292 AC: 4470 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3472

East Asian (EAS) AF: 0.225 AC: 1166 AN: 5176

South Asian (SAS) AF: 0.175 AC: 844 AN: 4822

European-Finnish (FIN) AF: 0.155 AC: 1640 AN: 10572

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12582 AN: 68006

Other (OTH) AF: 0.211 AC: 444 AN: 2108

Alfa AF: 0.183 Hom.: 886

Bravo AF: 0.193

TwinsUK AF: 0.185 AC: 687

ALSPAC AF: 0.181 AC: 697

ESP6500AA AF: 0.128 AC: 564

ESP6500EA AF: 0.185 AC: 1587

ExAC AF: 0.194 AC: 23502

Asia WGS AF: 0.191 AC: 663 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0044
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.0
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.12
ClinPred		0.0073	T
GERP RS		3.7
Varity_R		0.096
gMVP		0.084
Mutation Taster		=25/75	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.13
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: rs12944821; hg19: chr17-35956391;