chr21-44558297-G-C

Position:

• chr21-44558297-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198696.3(KRTAP10-3):​c.419C>G​(p.Ser140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,614,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: KRTAP10-3 NM_198696.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.350

Genes affected

KRTAP10-3 (HGNC:22968): (keratin associated protein 10-3) This gene encodes a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This gene encodes a member of the high sulfur KAP family. It is localized to a cluster of intronless KAPs at 21q22.3 which are located within the introns of the C21orf29 gene. [provided by RefSeq, Jul 2008]

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]

TSPEAR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07129726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-3	NM_198696.3	c.419C>G	p.Ser140Cys	missense_variant	1/1	ENST00000391620.2	NP_941969.2
TSPEAR	NM_144991.3	c.303+9488C>G		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.99+9488C>G		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-3	ENST00000391620.2	c.419C>G	p.Ser140Cys	missense_variant	1/1	6	NM_198696.3	ENSP00000375478.1
TSPEAR	ENST00000323084.9	c.303+9488C>G		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.258+9488C>G		intron_variant		1
TSPEAR	ENST00000642437.1	n.*248+9488C>G		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000454 AC: 114 AN: 251162 Hom.: 0 AF XY: 0.000457 AC XY: 62 AN XY: 135786

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000801

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1461822 Hom.: 1 Cov.: 191 AF XY: 0.000364 AC XY: 265 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000467 AC: 71 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74344

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000436

EpiControl AF: 0.000296

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

Feb 10, 2022

The c.419C>G (p.S140C) alteration is located in exon 1 (coding exon 1) of the KRTAP10-3 gene. This alteration results from a C to G substitution at nucleotide position 419, causing the serine (S) at amino acid position 140 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.062
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.088	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.069
Sift	Benign	0.11	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.24
MVP		0.36
MPC		0.022
ClinPred		0.099	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.039

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199514204; hg19: chr21-45978180;