rs778228977

Variant names:

• chr1-210241918-T-C
• rs778228977
• NM_019605.5:c.652T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019605.5(SERTAD4):​c.652T>C​(p.Ser218Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SERTAD4 NM_019605.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.303

Genes affected

SERTAD4 (HGNC:25236): (SERTA domain containing 4) Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041971356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERTAD4	NM_019605.5	c.652T>C	p.Ser218Pro	missense_variant	Exon 4 of 4	ENST00000367012.4	NP_062551.1
SERTAD4	NM_001375428.1	c.652T>C	p.Ser218Pro	missense_variant	Exon 4 of 4		NP_001362357.1
SERTAD4	NM_001354173.2	c.291+2310T>C		intron_variant	Intron 3 of 4		NP_001341102.1
SERTAD4	XM_047425536.1	c.291+2310T>C		intron_variant	Intron 3 of 4		XP_047281492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERTAD4	ENST00000367012.4	c.652T>C	p.Ser218Pro	missense_variant	Exon 4 of 4	1	NM_019605.5	ENSP00000355979.3
SERTAD4	ENST00000490620.5	n.856T>C		non_coding_transcript_exon_variant	Exon 4 of 4	4
SERTAD4	ENST00000482421.1	n.309+2310T>C		intron_variant	Intron 2 of 3	3
SERTAD4	ENST00000483884.1	n.158+3783T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250392 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.652T>C (p.S218P) alteration is located in exon 4 (coding exon 3) of the SERTAD4 gene. This alteration results from a T to C substitution at nucleotide position 652, causing the serine (S) at amino acid position 218 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	Benign	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.37	N
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.062
Sift	Benign	0.16	T
Sift4G	Benign	0.097	T
Polyphen		0.0010	B
Vest4		0.087
MutPred		0.098		Loss of phosphorylation at S218 (P = 0.0017);
MVP		0.043
MPC		0.13
ClinPred		0.069	T
GERP RS		2.8
Varity_R		0.096
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs778228977; hg19: chr1-210415263;