NM_003086.4:c.4342C>T

Variant names:

• chr9-136376424-G-A
• rs3812561
• NM_003086.4:c.4342C>T

Variant summary

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

The NM_003086.4(SNAPC4):​c.4342C>T​(p.Pro1448Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 1,613,488 control chromosomes in the GnomAD database, including 1,223 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (151 hom., cov: 34)
  • Exomes 𝑓: 0.034 (1072 hom.)
• Consequence: SNAPC4 NM_003086.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.285
• Publications: 37 publications found

Genes affected

SNAPC4 (HGNC:11137): (small nuclear RNA activating complex polypeptide 4) This gene encodes the largest subunit of the small nuclear RNA-activating protein (SNAP) complex. The encoded protein contains a Myb DNA-binding domain, and is essential for RNA polymerase II and III polymerase transcription from small nuclear RNA promoters. A mutation in this gene is associated with ankylosing spondylitis. [provided by RefSeq, Jul 2016]

SNAPC4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Baylor College of Medicine Research Center, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015933514).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003086.4. 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
	SNAPC4	NM_003086.4	MANE Select	c.4342C>T	p.Pro1448Ser	missense	Exon 23 of 24	NP_003077.2	Q5SXM2
	SNAPC4	NM_001394201.1		c.4342C>T	p.Pro1448Ser	missense	Exon 23 of 24	NP_001381130.1	Q5SXM2
	SNAPC4	NM_001394202.1		c.4258C>T	p.Pro1420Ser	missense	Exon 23 of 24	NP_001381131.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAPC4	ENST00000684778.1	MANE Select	c.4342C>T	p.Pro1448Ser	missense	Exon 23 of 24	ENSP00000510559.1	Q5SXM2
	SNAPC4	ENST00000298532.2	TSL:1	c.4342C>T	p.Pro1448Ser	missense	Exon 22 of 23	ENSP00000298532.2	Q5SXM2
	SNAPC4	ENST00000637388.2	TSL:5	c.4342C>T	p.Pro1448Ser	missense	Exon 23 of 24	ENSP00000490037.2	Q5SXM2

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6124 AN: 152198 Hom.: 150 Cov.: 34

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0310

GnomAD2 exomes AF: 0.0398 AC: 10003 AN: 251038 AF XY: 0.0396

Gnomad AFR exome AF: 0.0515

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.0438

Gnomad NFE exome AF: 0.0338

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0343 AC: 50061 AN: 1461172 Hom.: 1072 Cov.: 31 AF XY: 0.0345 AC XY: 25068 AN XY: 726892

African (AFR) AF: 0.0483 AC: 1618 AN: 33480

American (AMR) AF: 0.0125 AC: 560 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 791 AN: 26132

East Asian (EAS) AF: 0.101 AC: 3999 AN: 39698

South Asian (SAS) AF: 0.0410 AC: 3539 AN: 86252

European-Finnish (FIN) AF: 0.0455 AC: 2402 AN: 52834

Middle Eastern (MID) AF: 0.00937 AC: 54 AN: 5764

European-Non Finnish (NFE) AF: 0.0313 AC: 34843 AN: 1111908

Other (OTH) AF: 0.0373 AC: 2255 AN: 60382

GnomAD4 genome AF: 0.0403 AC: 6134 AN: 152316 Hom.: 151 Cov.: 34 AF XY: 0.0405 AC XY: 3017 AN XY: 74474

African (AFR) AF: 0.0494 AC: 2053 AN: 41568

American (AMR) AF: 0.0165 AC: 252 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3466

East Asian (EAS) AF: 0.113 AC: 587 AN: 5182

South Asian (SAS) AF: 0.0536 AC: 259 AN: 4832

European-Finnish (FIN) AF: 0.0454 AC: 482 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0338 AC: 2296 AN: 68024

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0347 Hom.: 410

Bravo AF: 0.0374

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0293 AC: 113

ESP6500AA AF: 0.0504 AC: 222

ESP6500EA AF: 0.0314 AC: 270

ExAC AF: 0.0406 AC: 4924

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.1
DANN	Benign	0.57
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.28
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.030
Sift	Benign	0.30	T
Sift4G	Benign	0.096	T
Polyphen		0.021	B
Vest4		0.11
ClinPred		0.00092	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.074
Mutation Taster		=98/2	polymorphism (auto)

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: rs3812561; hg19: chr9-139270876; COSMIC: COSV53733515; COSMIC: COSV53733515;