chr21-44658013-C-G

Position:

• chr21-44658013-C-G

Variant summary

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

The ENST00000323084.9(TSPEAR):​c.82+53420G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,528 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TSPEAR ENST00000323084.9 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.55

Genes affected

KRTAP12-3 (HGNC:20531): (keratin associated protein 12-3) Enables identical protein binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

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=0.045153737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP12-3	NM_198697.2	c.34C>G	p.Pro12Ala	missense_variant	1/1	ENST00000397907.1	NP_941970.2
TSPEAR	NM_144991.3	c.82+53420G>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+32532G>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP12-3	ENST00000397907.1	c.34C>G	p.Pro12Ala	missense_variant	1/1		NM_198697.2	ENSP00000381005	P1
TSPEAR	ENST00000323084.9	c.82+53420G>C		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000642437.1	c.*27+32532G>C		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461528 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Jul 11, 2023

The c.34C>G (p.P12A) alteration is located in exon 1 (coding exon 1) of the KRTAP12-3 gene. This alteration results from a C to G substitution at nucleotide position 34, causing the proline (P) at amino acid position 12 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	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.7
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.029
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.0080	B
Vest4		0.10
MutPred		0.29		Loss of glycosylation at T13 (P = 0.093);
MVP		0.040
MPC		0.93
ClinPred		0.065	T
GERP RS		-0.33
Varity_R		0.062
gMVP		0.035

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: chr21-46077930;