NM_198699.1:c.307G>T

Variant names:

• chr21-44697508-G-T
• rs782688897
• NM_198699.1:c.307G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_198699.1(KRTAP10-12):​c.307G>T​(p.Ala103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A103T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-12 NM_198699.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.509
• Publications: 0 publications found

Genes affected

KRTAP10-12 (HGNC:20533): (keratin associated protein 10-12) 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]

TSPEAR Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030512184).
• BP6: Variant 21-44697508-G-T is Benign according to our data. Variant chr21-44697508-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2611112.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198699.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-12	NM_198699.1	MANE Select	c.307G>T	p.Ala103Ser	missense	Exon 1 of 1	NP_941972.1	P60413
	TSPEAR	NM_144991.3	MANE Select	c.82+13925C>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-184-6902C>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-12	ENST00000400365.3	TSL:6 MANE Select	c.307G>T	p.Ala103Ser	missense	Exon 1 of 1	ENSP00000383216.3	P60413
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+13925C>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+13925C>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 148758 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461688 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 148758 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72498

African (AFR) AF: 0.00 AC: 0 AN: 40082

American (AMR) AF: 0.00 AC: 0 AN: 15014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5034

South Asian (SAS) AF: 0.00 AC: 0 AN: 4650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67062

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.28
DANN	Benign	0.78
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.0087	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.51
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.023
Sift	Benign	0.68	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.089
MutPred		0.28		Gain of glycosylation at A103 (P = 0.0115)
MVP		0.014
MPC		0.25
ClinPred		0.047	T
GERP RS		-6.2
PromoterAI		-0.12	Neutral
Varity_R		0.042
gMVP		0.030
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs782688897; hg19: chr21-46117423;