4-39556491-G-T

Variant names:

• chr4-39556491-G-T
• NM_174921.3:c.204C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_174921.3(SMIM14):​c.204C>A​(p.Phe68Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMIM14 NM_174921.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

SMIM14 (HGNC:27321): (small integral membrane protein 14) Predicted to act upstream of or within blastocyst hatching. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

UGDH-AS1 (HGNC:40601): (UGDH antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31496945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMIM14	NM_174921.3	c.204C>A	p.Phe68Leu	missense_variant	Exon 4 of 5	ENST00000295958.10	NP_777581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMIM14	ENST00000295958.10	c.204C>A	p.Phe68Leu	missense_variant	Exon 4 of 5	1	NM_174921.3	ENSP00000295958.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.204C>A (p.F68L) alteration is located in exon 4 (coding exon 3) of the SMIM14 gene. This alteration results from a C to A substitution at nucleotide position 204, causing the phenylalanine (F) at amino acid position 68 to be replaced by a leucine (L). 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	0.95
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.020	D;.
Polyphen		0.81	P;.
Vest4		0.63
MutPred		0.31		Gain of catalytic residue at F68 (P = 0.0288);Gain of catalytic residue at F68 (P = 0.0288);
MVP		0.33
MPC		1.5
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.38
gMVP		0.75

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: chr4-39558111;