14-74409384-A-G

Position:

• chr14-74409384-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001105579.2(SYNDIG1L):​c.361T>C​(p.Ser121Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNDIG1L NM_001105579.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46

Genes affected

SYNDIG1L (HGNC:32388): (synapse differentiation inducing 1 like) Predicted to be located in Golgi apparatus. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNDIG1L	NM_001105579.2	c.361T>C	p.Ser121Pro	missense_variant	2/4	ENST00000331628.8	NP_001099049.1
SYNDIG1L	XM_017021600.2	c.361T>C	p.Ser121Pro	missense_variant	2/4		XP_016877089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNDIG1L	ENST00000331628.8	c.361T>C	p.Ser121Pro	missense_variant	2/4	5	NM_001105579.2	ENSP00000331474	P1
SYNDIG1L	ENST00000554823.1	c.361T>C	p.Ser121Pro	missense_variant	1/3	3		ENSP00000450439	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.361T>C (p.S121P) alteration is located in exon 2 (coding exon 1) of the SYNDIG1L gene. This alteration results from a T to C substitution at nucleotide position 361, causing the serine (S) at amino acid position 121 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N;N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.35		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.89
MPC		1.1
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.34
gMVP		0.79

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-74876087;