NM_198687.2:c.355T>C

Variant names:

• chr21-44574113-T-C
• rs79601471
• NM_198687.2:c.355T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_198687.2(KRTAP10-4):​c.355T>C​(p.Cys119Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,589,926 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (13 hom., cov: 36)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0510
• Publications: 2 publications found

Genes affected

KRTAP10-4 (HGNC:20521): (keratin associated protein 10-4) This is an intronless gene located in a cluster of related genes on the q arm of chromosome 21. The proteins encoded by these genes form disulfide bonds with cysteine residues in hair keratins, thereby contributing to the structure and stability of hair fibers. [provided by RefSeq, Apr 2014]

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hearing loss, autosomal recessive

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

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036812723).
• BP6: Variant 21-44574113-T-C is Benign according to our data. Variant chr21-44574113-T-C is described in ClinVar as Benign. ClinVar VariationId is 377329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198687.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-4	NM_198687.2	MANE Select	c.355T>C	p.Cys119Arg	missense	Exon 1 of 1	NP_941960.2
	TSPEAR	NM_144991.3	MANE Select	c.83-6108A>G		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-6108A>G		intron	N/A	NP_001258966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-4	ENST00000400374.4	TSL:6 MANE Select	c.355T>C	p.Cys119Arg	missense	Exon 1 of 1	ENSP00000383225.3
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-6108A>G		intron	N/A	ENSP00000321987.4
	TSPEAR	ENST00000943283.1		c.83-6108A>G		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5297 AN: 147972 Hom.: 13 Cov.: 36

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.00981 AC: 2444 AN: 249212 AF XY: 0.00733

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00647

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00706

GnomAD4 exome AF: 0.00386 AC: 5571 AN: 1441850 Hom.: 19 Cov.: 176 AF XY: 0.00336 AC XY: 2413 AN XY: 717360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.146 AC: 4482 AN: 30602

American (AMR) AF: 0.00746 AC: 327 AN: 43840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38778

South Asian (SAS) AF: 0.000199 AC: 17 AN: 85264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52636

Middle Eastern (MID) AF: 0.00636 AC: 36 AN: 5664

European-Non Finnish (NFE) AF: 0.000136 AC: 150 AN: 1100506

Other (OTH) AF: 0.00947 AC: 559 AN: 59022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0360 AC: 5326 AN: 148076 Hom.: 13 Cov.: 36 AF XY: 0.0353 AC XY: 2561 AN XY: 72482

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.131 AC: 4974 AN: 37902

American (AMR) AF: 0.0174 AC: 263 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67934

Other (OTH) AF: 0.0289 AC: 60 AN: 2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0232 Hom.: 0

ESP6500AA AF: 0.113 AC: 498

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0154 AC: 1874

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.82
Eigen	Benign	0.063
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.051
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Vest4		0.16
MPC		0.80
ClinPred		0.078	T
GERP RS		3.2
PromoterAI		-0.0042	Neutral
gMVP		0.34
Mutation Taster		=100/0	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: rs79601471; hg19: chr21-45993990; COSMIC: COSV99064393; COSMIC: COSV99064393;