rs11978706

Variant names:

• chr7-6190493-G-C
• rs11978706
• NM_004227.4:c.73C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-6190493-G-C
• chr7-6190493-G-A
• chr7-6190493-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001367580.1(CYTH3):​c.-1105C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000731 in 1,505,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CYTH3 NM_001367580.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.427
• Publications: 2 publications found

Genes affected

CYTH3 (HGNC:9504): (cytohesin 3) This gene encodes a member of the PSCD (pleckstrin homology, Sec7 and coiled-coil domains) family. PSCD family members have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein (GEP) activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family appear to mediate the regulation of protein sorting and membrane trafficking. This encoded protein is involved in the control of Golgi structure and function, and it may have a physiological role in regulating ADP-ribosylation factor protein 6 (ARF) functions, in addition to acting on ARF1. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03443429).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367580.1. 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
	CYTH3	NM_004227.4	MANE Select	c.73C>G	p.Leu25Val	missense	Exon 2 of 13	NP_004218.1	O43739-2
	CYTH3	NM_001367580.1		c.-1105C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001354509.1	B7Z2V9
	CYTH3	NM_001367581.1		c.-652C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001354510.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH3	ENST00000350796.8	TSL:1 MANE Select	c.73C>G	p.Leu25Val	missense	Exon 2 of 13	ENSP00000297044.7	O43739-2
	CYTH3	ENST00000898314.1		c.211C>G	p.Leu71Val	missense	Exon 3 of 14	ENSP00000568373.1
	CYTH3	ENST00000898313.1		c.166C>G	p.Leu56Val	missense	Exon 3 of 14	ENSP00000568372.1

Frequencies

GnomAD3 genomes AF: 0.0000484 AC: 7 AN: 144586 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1361210 Hom.: 0 Cov.: 34 AF XY: 0.00000149 AC XY: 1 AN XY: 671860

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

African (AFR) AF: 0.0000997 AC: 3 AN: 30102

American (AMR) AF: 0.00 AC: 0 AN: 29836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24454

East Asian (EAS) AF: 0.00 AC: 0 AN: 34798

South Asian (SAS) AF: 0.00 AC: 0 AN: 75380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1067492

Other (OTH) AF: 0.00 AC: 0 AN: 56584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000396870), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000484 AC: 7 AN: 144586 Hom.: 0 Cov.: 30 AF XY: 0.0000575 AC XY: 4 AN XY: 69550

African (AFR) AF: 0.000153 AC: 6 AN: 39204

American (AMR) AF: 0.00 AC: 0 AN: 14016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 4798

South Asian (SAS) AF: 0.00 AC: 0 AN: 4582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66964

Other (OTH) AF: 0.00 AC: 0 AN: 1986

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.63
DANN	Benign	0.89
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.43
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.020
Sift	Benign	0.29	T
Sift4G	Benign	0.30	T
Polyphen		0.065	B
Vest4		0.076
MVP		0.17
MPC		0.058
ClinPred		0.30	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.22
Mutation Taster		=94/6	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: rs11978706; hg19: chr7-6230124;