NM_145865.3:c.1021G>A

Variant names:

• chr16-21250587-G-A
• rs201951492
• NM_145865.3:c.1021G>A

Variant summary

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

The NM_145865.3(ANKS4B):​c.1021G>A​(p.Asp341Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: ANKS4B NM_145865.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

Genes affected

ANKS4B (HGNC:26795): (ankyrin repeat and sterile alpha motif domain containing 4B) Involved in brush border assembly; cellular protein-containing complex assembly; and protein localization to microvillus. Located in brush border and microvillus. [provided by Alliance of Genome Resources, Apr 2022]

CRYM (HGNC:2418): (crystallin mu) Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles. Mutations in this gene have been associated with autosomal dominant non-syndromic deafness. [provided by RefSeq, Sep 2014]

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=0.20239004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKS4B	NM_145865.3	c.1021G>A	p.Asp341Asn	missense_variant	Exon 2 of 2	ENST00000311620.7	NP_665872.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKS4B	ENST00000311620.7	c.1021G>A	p.Asp341Asn	missense_variant	Exon 2 of 2	1	NM_145865.3	ENSP00000308772.5
CRYM	ENST00000574448.5	n.*521-6519C>T		intron_variant	Intron 8 of 9	1		ENSP00000459982.1
CRYM	ENST00000570401.5	c.263-6519C>T		intron_variant	Intron 3 of 3	5		ENSP00000460820.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000213 AC: 53 AN: 249142 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000523 AC: 765 AN: 1461888 Hom.: 1 Cov.: 31 AF XY: 0.000474 AC XY: 345 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74338

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.000829 AC: 7

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1021G>A (p.D341N) alteration is located in exon 2 (coding exon 2) of the ANKS4B gene. This alteration results from a G to A substitution at nucleotide position 1021, causing the aspartic acid (D) at amino acid position 341 to be replaced by an asparagine (N). 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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D
Sift4G	Benign	0.15	T
Polyphen		0.95	P
Vest4		0.27
MVP		0.89
MPC		0.63
ClinPred		0.31	T
GERP RS		6.1
Varity_R		0.15
gMVP		0.073

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

LitVar

Other links and lift over

dbSNP: rs201951492; hg19: chr16-21261908;