14-74407575-A-G

Position:

• chr14-74407575-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001105579.2(SYNDIG1L):​c.677T>C​(p.Val226Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNDIG1L NM_001105579.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNDIG1L	NM_001105579.2	c.677T>C	p.Val226Ala	missense_variant	4/4	ENST00000331628.8	NP_001099049.1
SYNDIG1L	XM_017021600.2	c.677T>C	p.Val226Ala	missense_variant	4/4		XP_016877089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNDIG1L	ENST00000331628.8	c.677T>C	p.Val226Ala	missense_variant	4/4	5	NM_001105579.2	ENSP00000331474	P1
SYNDIG1L	ENST00000554823.1	c.677T>C	p.Val226Ala	missense_variant	3/3	3		ENSP00000450439	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 22, 2024

The c.677T>C (p.V226A) alteration is located in exon 4 (coding exon 3) of the SYNDIG1L gene. This alteration results from a T to C substitution at nucleotide position 677, causing the valine (V) at amino acid position 226 to be replaced by an alanine (A). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.064	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.35		Gain of catalytic residue at V224 (P = 0);Gain of catalytic residue at V224 (P = 0);
MVP		0.86
MPC		1.1
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.28
gMVP		0.88

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: chr14-74874278;