NM_000394.4:c.161G>A

Variant names:

• chr21-43169260-G-A
• rs777728814
• NM_000394.4:c.161G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP2 PP3

The NM_000394.4(CRYAA):​c.161G>A​(p.Arg54His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 9)
  • Exomes 𝑓: 0.000021 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.25
• Publications: 10 publications found

Genes affected

CRYAA (HGNC:2388): (crystallin alpha A) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]

CRYAA Gene-Disease associations (from GenCC):

• cataract 9 multiple types

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset anterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC107987300 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a chain Alpha-crystallin A(1-172) (size 171) in uniprot entity CRYAA_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000394.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43169259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.34778 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset lamellar cataract, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset anterior polar cataract, total early-onset cataract, cataract 9 multiple types.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.161G>A	p.Arg54His	missense_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1	n.546+1777C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6	c.161G>A	p.Arg54His	missense_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2
CRYAA	ENST00000482775.1	n.174G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 1 AN: 75758 Hom.: 0 Cov.: 9

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248326 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000207 AC: 15 AN: 724496 Hom.: 3 Cov.: 9 AF XY: 0.0000186 AC XY: 7 AN XY: 376148

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

African (AFR) AF: 0.00 AC: 0 AN: 16612

American (AMR) AF: 0.00 AC: 0 AN: 35008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17784

East Asian (EAS) AF: 0.00 AC: 0 AN: 37128

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70712

European-Finnish (FIN) AF: 0.0000676 AC: 2 AN: 29566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2816

European-Non Finnish (NFE) AF: 0.0000250 AC: 12 AN: 479828

Other (OTH) AF: 0.00 AC: 0 AN: 35042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.017003), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 1 AN: 75758 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 36438

African (AFR) AF: 0.00 AC: 0 AN: 18550

American (AMR) AF: 0.00 AC: 0 AN: 8108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1940

East Asian (EAS) AF: 0.00 AC: 0 AN: 3948

South Asian (SAS) AF: 0.00 AC: 0 AN: 2656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.0000296 AC: 1 AN: 33824

Other (OTH) AF: 0.00 AC: 0 AN: 880

Alfa AF: 0.0000659 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.079	T
Polyphen		0.95	P
Vest4		0.48
MVP		0.91
MPC		1.3
ClinPred		0.87	D
GERP RS		4.9
PromoterAI		-0.056	Neutral
Varity_R		0.35
gMVP		0.69
Mutation Taster		=30/70	disease causing

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: rs777728814; hg19: chr21-44589370; COSMIC: COSV99374880; COSMIC: COSV99374880;