rs370885897

Variant names:

• chr10-99533384-T-G
• rs370885897
• NM_145285.3:c.253T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_145285.3(NKX2-3):​c.253T>G​(p.Ser85Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,608,776 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NKX2-3 NM_145285.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.379
• Publications: 0 publications found

Genes affected

NKX2-3 (HGNC:7836): (NK2 homeobox 3) This gene encodes a homeodomain-containing transcription factor. The encoded protein is a member of the NKX family of homeodomain transcription factors. Studies of similar proteins in mouse and rat have indicated a potential role in cellular differentiation.[provided by RefSeq, Mar 2010]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048499465).
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145285.3. 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
	NKX2-3	NM_145285.3	MANE Select	c.253T>G	p.Ser85Ala	missense	Exon 1 of 2	NP_660328.2	Q8TAU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-3	ENST00000344586.9	TSL:2 MANE Select	c.253T>G	p.Ser85Ala	missense	Exon 1 of 2	ENSP00000342828.7	Q8TAU0

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236200 AF XY: 0.00

Gnomad AFR exome AF: 0.0000688

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000549 AC: 8 AN: 1456494 Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3 AN XY: 723994

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 43396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110202

Other (OTH) AF: 0.0000830 AC: 5 AN: 60254

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74460

African (AFR) AF: 0.000144 AC: 6 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000500 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.065
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PhyloP100		0.38
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.026
Sift	Benign	0.28	T
Sift4G	Benign	0.91	T
Polyphen		0.0010	B
Vest4		0.087
MVP		0.32
ClinPred		0.027	T
GERP RS		-0.85
PromoterAI		-0.036	Neutral
Varity_R		0.066
gMVP		0.14
Mutation Taster		=96/4	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: rs370885897; hg19: chr10-101293141;